11

Research 

on Cocaine
NN0066

Research 

on Cocaine
ii

Introduction

The National Institute on Drug Abuse (NIDA) supports most of the world’s research on drug abuse and addiction. 

NIDA-funded research enables scientists to apply the most advanced techniques available to the study of every aspect 

of drug abuse, including:

• genetic and social determinants of vulnerability and response to drugs;

• short- and long-term effects of drugs on the brain, including addiction;

• other health and social impacts of drug abuse, including infectious diseases and economic costs;

• development and testing of medication and behavioral treatments for abuse and addiction; and

• development and evaluation of effective messages to deter young people, in particular, from abusing drugs.

Included in this document are selections of topic-specific articles reprinted from NIDA’s research newsletter, 

NIDA NOTES. Six times per year, NIDA NOTES reports on important highlights from NIDA-sponsored research, 

in a format that specialists and lay readers alike can read and put to use. Selections like the current one are intended 

to remind regular NIDA NOTES readers and inform other readers of important research discoveries during the periods 

they cover.

We hope the information contained here answers your needs and interests. To subscribe to NIDA NOTES and for 

further information on NIDA’s drug abuse and addiction research, please visit our Web site at www.drugabuse.gov.
iii

Table of Contents

Cocaine Locks Rates Into Unrewarding Behaviors 

(V22–3; April 2009) ......................................................1

Low Dopamine Receptor Availability May Promote 

Cocaine Addiction (V22–3; April 2009)........................5

Aripiprazole Prevents Rats From Resuming Cocaine 

Seeking (V22–2; December 2008).................................8

Long-Term Cocaine Self-Administration Depresses 

Brain Activity (V22–2; December 2008) .....................10

Methadone Reduces Rats’ Cocaine Seeking 

(V22–2; December 2008)............................................12

Brain Proteins Differ in Cocaine-Overdose Victims 

(V22–2; December 2008)............................................15

Fewer Young Adults Abuse Cocaine and 

Methamphetamine, National Survey Finds 

(V22–2; December 2008)............................................16

Mice With Genetic Alteration Eschew Cocaine 

(V21–6; June 2008).....................................................18

Long-Term Cocaine Abuse Linked With Impaired 

Heart Function (V21–5; March 2008) ........................20

Cocaine Can Mobilize Stored Dopamine 

(V21–5; March 2008)..................................................20

Chronic Cocaine Abusers Have Occult Insomnia in 

Early Abstinence (V21–5; March 2008).......................21

Neuropeptide Promotes Drug-Seeking and Craving in 

Rats (V21–4; October 2007) .......................................23

Gene Experiment Confirms a Suspected Cocaine 

Action (V21–4; October 2007)....................................25

Impacts of Drugs on Neurotransmission 

(V21–4; October 2007) ...............................................28 

Serotonin System May Have Potential as a Target for 

Cocaine Medications (V21–3; April 2007) ..................33

Brain Changes Accompany Cocaine Withdrawal 

(V21–2; February 2007) ............................................. 35

Cocaine Craving Activates Brain Reward 

Structures; Cocaine “High” Dampens Them 

(V21–2; February 2007) ..............................................36 

Cocaine Abusers’ Pretreatment Cue Responses Predict 

Recovery Success (V21–2; February 2007)...................38 

Behavioral Response to Novelty Foreshadows 

Neurological Response to Cocaine 

(V21–2; February 2007) ..............................................41 

Methylphenidate for Comorbid Cocaine Abuse, 

ADHD (V21–1; October 2006)................................. 43

Brain Mechanism Turns Off Cocaine Related 

Memory in Rats (V21–1; October 2006).................... 44

Nicotine and Cocaine Vaccines Move Forward 

(V20–5; April 2006) ................................................... 47

Cocaine Abuse and HIV Are Linked With Coronary 

Calcification (V20–5; April 2006) .............................. 48

Modafinil Improves Behavioral Therapy Results In 

Cocaine (V20–3; October 2005) .................................50 

Disulfiram Reduces Cocaine Abuse 

(V20–2; August 2005) .................................................52 

Genetic Engineering Reveals Proteins’ Key Role in 

Sensitivity to Cocaine (V20–2; August 2005)............. 55

Researchers Investigate Cocaine “Abstinence 

Syndrome” (V20–1; August 2005).............................. 56

Cocaine-Related Environmental Cues Elicit Physiological 

Stress Responses (V20–1; August 2005)...................... 58

A Single Cocaine “Binge” Can Establish 

Long-Term Cue-Induced Drug-Seeking in Rats 

(V19–6; May 2005).................................................... 61

Topiramate Shows Promise in Cocaine Addiction 

(V19–6; May 2005).................................................... 63

Men and Women May Process Cocaine Cues 

Differently (V19–4; December 2004)......................... 65

Sigma Antagonists: Potential Cocaine Medications 

With Novel Activity (V19–4; December 2004) .......... 67

Behavioral Modification Changes the Brain’s 

Biochemical Response to Cocaine, Curbs Relapse 

Caused by Stress (V19–3; September 2004)................ 69

Brain Glutamate Concentrations Affect Cocaine 

Seeking (V19–3; September 2004).............................. 71

Cocaine Abusers’ Cognitive Deficits Compromise 

Treatment Outcomes (V19–1; April 2004)..................73 

The Long Road to Medication Development: 

Cocaine Treatment Moves to Clinical Trials 

(V18–6; February 2004) ..............................................75 

Cocaine May Compromise Immune System, 

Increase Risk of Infection (V18–6; February 2004) .... 78

New Animal Model Simulates Human Exposure, 

Confirms Harm From Prenatal Cocaine 

(V18–1; June 2003).................................................... 79
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Joint Treatment of PTSD and Cocaine Abuse May 

Reduce Severity of Both Disorders 

(V18–1; June 2003).................................................... 81

Researchers Probe for Clues to ADHD Medications’ 

Protective Effects (V18–1; June 2003)........................ 83

Cocaine’s Effect on Blood Components May Be Linked 

to Heart Attack and Stroke (V17–6; March 2003) ..... 86

Study Finds Significant Mental Deficits in Toddlers 

Exposed to Cocaine Before Birth 

(V17–5; January 2003) ............................................... 88

Social Environment Appears Linked to Biological 

Changes in Dopamine System, May Influence 

Vulnerability to Cocaine Addiction 

(V17–5; January 2003) ................................................90 

Study Opens Promising New Approach to Developing 

Medications To Prevent Relapse to Cocaine Use 

(V17–3; October 2002) ...............................................92 

Cocaine’s Effects on Cerebral Blood Flow Differ 

Between Men and Women (V17–2; May 2002)......... 94

Blood Pressure Medication May Improve Cocaine 

Treatment Results in Patients With Severe Withdrawal 

Symptoms (V16–6; February 2002)............................ 96

Methamphetamine, Cocaine Abusers Have Different 

Patterns of Drug Use, Suffer Different Cognitive 

Impairments (V16–5; December 2001)...................... 98

Altered Cellular Activity May Be First Step in 

Progression to Cocaine Addiction 

(V16–5; December 2001)......................................... 100

Biochemical Brain Abnormality Found in School-Age 

Children Prenatally Exposed to Cocaine 

(V16–4; October 2001) ............................................ 102

Even Modest Cocaine Use May Cause Brain 

Changes That Could Contribute to Addiction 

(V16–3; August 2001) .............................................. 104

Cues for Cocaine and Normal Pleasures Activate 

Common Brain Sites (V16–2; May 2001)................ 106

Alcohol-Treatment Medication May Help Reduce 

Cocaine Abuse Among Heroin Treatment Patients 

(V16–1; March 2001)............................................... 108

Nicotine Craving and Heavy Smoking May 

Contribute to Increased Use of Cocaine and Heroin 

(V15–5; October 2000) ............................................ 110

Potential Cocaine Medications Show Effectiveness 

Against Psychosis, Seizures (V14–6; March 2000) .... 112

Combining Drug Counseling Methods Proves 

Effective in Treating Cocaine Addiction 

(V14–5; December 1999)......................................... 114

Research Shows Effects of Prenatal Cocaine 

Exposure Are Subtle But Significant 

(V14–3; September 1999)......................................... 116

NIDA Studies Clarify Developmental Effects of 

Prenatal Cocaine Exposure 

(V14–3; September 1999)..........................................118 

Cocaine’s Pleasurable Effects May Involve Multiple 

Chemical Sites In the Brain 

(V14–2; August 1999) .............................................. 121

Blood-borne Medications Could Intercept Drugs 

Before They Reach the Brain 

(V14–2; August 1999) .............................................. 124

Coping Skills Help Patients Recognize and Resist the 

Urge to Use Cocaine (V13–6; March 1999)............. 127

Cocaine Activates Different Brain Regions for Rush 

Versus Craving (V13–5; February 1999) ...................128 

Cocaine Abuse May Lead To Strokes and Mental 

Deficits (V13–3; July 1998)...................................... 130

Brain Scans Open Window To View Cocaine’s 

Effects on the Brain (V13–2; July 1998)................... 133

NIDA Brain Imaging Research Links Cue-Induced 

Craving to Structures Involved in Memory 

(V11–5; November/December 1996) ....................... 135

Anxiety and Stress Found to Promote Cocaine Use 

in Rats (V11–4; September/October 1996) ...............137

Cocaine Affects Men and Women Differently, NIDA 

Study Shows (V11–1; January/February 1996)......... 139

Inner-City Cocaine Abusers in Baltimore Respond to 

Voucher-Based Treatment 

(V10–5; September/October 1995) .......................... 141

Voucher System Is Effective Tool in Treating Cocaine 

Abuse (V10–5; September/October 1995)................ 143

NIDA-Supported Scientists Identify Receptor 

Associated with Cocaine Abuse 

(V10–5; September/October 1995) .......................... 146
Research Findings

Volume #, Number (Month Year)

1

Cocaine Locks Rats Into Unrewarding Behaviors

Brain circuits that guide behavior by registering consequences become less flexible after drug exposure.

By NIDA Notes Staff

Research Findings

Volume 22, Number 3 (April 2009)

People initially take cocaine for pleasure, but for most 

chronic abusers, the high becomes progressively shorter 

and weaker, and negative social and economic consequences grow increasingly dire. Relationships hit the 

rocks, financial problems mount, and legal trouble follows, but the cocaine abuser often fails to adapt his or her 

behavior to avoid the accumulating personal disasters and 

instead remains stuck in self-damaging patterns.

New NIDA-funded research with rats indicates that 

cocaine may contribute to this inflexibility by impeding 

abusers’ ability to associate warning signs with outcomes. 

The research links successful sign reading to two connected brain structures—the orbitofrontal cortex (OFC), 

located directly above the eye sockets, and the basolateral 

amygdala (ABL), deep in the brain. Cocaine appears to 

weaken neural signaling in these structures.

“Our findings may explain why cocaine abusers and 

cocaine-exposed animals have difficulty adapting their 

behavior 

to avoid 

negative outcomes,” says 

Dr. Geoffrey 

Schoenbaum, 

who led the 

University 

of Maryland 

School of 

Medicine 

studies. 

“Cocaine 

seems to 

disrupt the 

informationprocessing 

ability of 

neurons in a 

learning circuit that helps animals and people accommodate their behavior when the environment changes.”

Learning To Use Cues

To test cocaine’s impact on learning and adaptation, Dr. 

Schoenbaum and colleagues used a protocol called the 

two-odor go/no-go discrimination task (see box). The protocol consists of two parts. The first tests an animal’s ability to link cues to desired and aversive outcomes. It challenges the animal to perform a task analogous to that of a 

person learning that right-hand faucets deliver cold water 

and left-hand ones, hot. In Dr. Schoenbaum’s protocol, 

the counterparts to the faucets are odors. The researchers 

give a rat a whiff of one odor immediately before filling a 

well in the cage with a delectable sucrose-flavored drink, 

and they provide another odor when the well is about to 

be filled with a repugnant, quinine-flavored concoction. 

The rats have to learn to use both cues to obtain the sweet 

drink and shun the nasty one.

The second part of the go/no-go protocol tests rats’ ability 

to adjust when cues change their meanings. The odor that 

formerly indicated the sweet drink now signals the bitter 

one, and vice versa. This put the animals into a situation 

analogous to that of a person whose inattentive plumber 

crossed the pipes leading to a sink’s faucets. A person in 

this predicament must quickly learn to change expectations or risk repeated scaldings.

Dr. Schoenbaum’s team ran two groups of rats through 

the go/no-go protocol. One group had been exposed to 

cocaine daily for 2 weeks one month prior to the protocol, and the other was drug-free. In the first part of the 

protocol, both groups readily learned to discriminate 

between the odor cues. After a dozen trials, both groups 

consistently—though not unerringly—went to the well 

following the cue for sweet and shunned it following the 

cue for bitter.

One observation during the first part of the protocol 

suggested that, despite their similar learning curves, the 

cocaine-exposed rats had reduced sensitivity to cues predicting negative experiences. The behavior of the rats 

in the two groups differed in those occasional instances 

where rats mistakenly went to the well following the cue 

for the bitter drink. The drug-naïve animals hesitated 

before setting off, suggesting that they had some inkling 

that the consequences might not be desirable. The drugexposed animals, in contrast, rushed right to the well.

In the second part of the protocol, cocaine markedly 

reduced some rats’ ability to adapt to the switched odordrink pairings. The drug-naïve rats and half of the drugexposed rats learned to reverse their responses to the cues 

1
2

after an average of 28 trials. The other half of the drugexposed rats, however, required 35 trials.

Neuron Flexibility

The cocaine-exposed rats’ poorer performance in the go/

no-go protocols suggested that the drug impairs neurons 

in a brain circuit that links cues to the expectation of satisfaction or dissatisfaction. When a person or an animal 

responds to a cue—whether it be the position of a faucet 

or an odor—these neurons encode whether the experience 

that follows feels good or bad. In subsequent encounters 

with the cue, some neurons increase their firing rate if past 

responses led to a satisfying experience; others increase 

their firing rate if past responses caused aversive or disappointing outcomes.

“The firing of these neurons represents the linking of 

the cue to an expectation of an outcome, based on previous experience,” says Dr. Schoenbaum. “We believe that 

at the time an animal has to decide whether or how to 

respond, these expectations influence its decision.”

To test the hypothesis that cocaine exposure affects these 

outcome-expectant neurons, the research teams ran rats 

through go/no-go protocols while monitoring the animals’ 

neuronal activity in two brain areas: the OFC and ABL. 

The OFC is part of the brain’s decisionmaking circuit; its 

neuronal activity has been associated with stimulant addiction and craving. The ABL is part of the brain’s emotional 

circuit. In previous studies, people with a damaged OFC 

or ABL were slow to change response patterns after consequences had changed from rewarding to adverse. This 

behavior resembles that of chronic cocaine abusers—and 

also some of the cocaine-exposed rats in the team’s earlier 

experiment.

In both cocaine-exposed and unexposed rats, electrode 

recordings taken during the first part of the protocol 

showed that about 19 percent of the neurons monitored 

in the OFC and 26 percent of those in the ABL developed 

outcome-expectant firing patterns. This finding is consistent with the observation that the two groups of animals 

learned equally well to use the initial cues to guide their 

drinking.

Nevertheless, the two groups’ neuronal responses may 

help explain why, on those occasions when the rats mistakenly responded to the quinine cue, the cocaine-exposed 

rats went directly to the well while the unexposed rats hesitated. The recordings revealed that the exposed rats’ OFC 

quinine-predicting neurons failed to activate in response 

to the odor.

In the second part of the go/no-go 

protocol, the cocaine-exposed animals’ 

slower adaptation correlated with 

reduced flexibility of outcome-expectant 

neurons. When the researchers reversed 

the odor cues, neurons predicting sweet 

and bitter must switch their responses 

to continue to support decisions leading 

to happy drinking experiences.

Yet approximately 27 percent of those 

neurons in the ABL of the drug-exposed 

rats failed to make the switch—

compared with only approximately 3 

percent in the drug-free rats. The ABL 

neurons of the drug-exposed rats that 

initially signaled favorable expectations 

proved more inflexible than those that 

signaled unfavorable expectations.

A Model for Decisionmaking

Dr. Schoenbaum’s results led him to 

propose a model to explain how the 

ABL and OFC interact in cue response 

decisions. In this schema, when an individual encounters a familiar cue, ABL 

outcome-expectant neurons send the 

OFC a “good/go” or “bad/don’t-go” 

message, or no message at all. The OFC 

combines this message with information 
3

arriving from other brain areas to form a comprehensive 

picture of the likely consequences of acting.

“By weakening the responses of these 

frontal cortex areas, chronic cocaine 

use may make people more prone to 

relapse and compulsive drug-seeking.” 

—Dr. Geoffrey Schoenbaum

This picture becomes the basis for a decision to respond 

to the cue or refrain. If the individual does respond, the 

OFC then compares the resulting consequences with the 

picture and notifies the ABL whether the latest data confirm or contradict the expectation. Completing the cycle, 

the ABL outcome-expectant neurons use this feedback to 

adjust their future responses to the cue.

The key to cocaine abusers’ persistent self-defeating behaviors is the drug’s interference with the last step in this 

cycle, Dr. Schoenbaum says. Feedback from the OFC is 

weakened by drug exposure; consequently, ABL outcome-
4

expectant neurons fail to change their responses. Instead, 

they persist in established firing patterns, continuing to 

signal outdated information to the OFC, and become a 

hindrance rather than a help to good decisionmaking.

“Cocaine renders the OFC and other frontal cortex areas’ 

messages about likely outcomes less effective. Such signals 

both guide behavior and facilitate learning when things 

don’t go as expected. By weakening the responses of these 

frontal cortex areas, chronic cocaine use may make people 

more prone to relapse and compulsive drug-seeking,” says 

Dr. Schoenbaum.

“A person in drug abuse treatment is trying to change his 

or her behavior, yet these animal findings suggest that 

cocaine exposure ossifies a neural circuit likely involved in these changes,” 

says Dr. Susan Volman of NIDA’s 

Division of Basic Neuroscience and 

Behavioral Research. “Scientists may 

someday develop medications that 

enhance neural flexibility and facilitate 

reengagement of cognitive circuits, 

which would help behavioral therapy 

lessons sink in.”

Dr. Elliot Stein of NIDA’s Intramural 

Research Program, who is performing 

brain imaging of cocaine abusers as 

they do reversal learning tasks, agrees: 

“If the drug-exposed brain lacks plasticity for new learning, then restoring 

the functional integrity of the circuit may increase the 

effectiveness of behavioral interventions.”

Sources

• Stalnaker, T.A., et al. Abnormal associative encoding in orbitofrontal neurons in cocaine-experienced 

rats during decision-making. European Journal of 

Neuroscience 24(9):2643-2653, 2006. 

• Stalnaker, T.A., et al. Cocaine-induced decision-making deficits are mediated by miscoding in basolateral 

amygdala. Nature Neuroscience 10(8):949-951, 2007.
Research Findings

Volume #, Number (Month Year)

5

Low Dopamine Receptor Availability May Promote Cocaine 

Addiction 

Reduced availability heightens reinforcing effects of cocaine in monkeys, and the drug drives this measure 

even lower.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 22, Number 3 (April 2009)

In a study with rhesus monkeys, Dr. Michael Nader and 

colleagues at Wake Forest University recently showed that 

cocaine lowers availability of the dopamine D2

 receptors 

in the basal ganglia—the brain region that includes key 

components of the reward system. The consequences may 

include addiction-promoting alterations in cognitive functioning and decisionmaking.

Dr. Nader’s study also confirms previous findings that 

individual animals with lower D2 receptor availability are 

especially responsive to cocaine’s reinforcing effects.

In a promising finding for people trying to recover from 

cocaine addiction, receptor availability levels in some of 

the monkeys recovered after less than a year of abstaining 

from drug use.

Receptor Availability and Cocaine Exposure

The D2

 receptor resides in the outer membrane of brain 

cells that shape motivation and emotion, thought, and 

movement. The receptor protein enables the neurotransmitter dopamine to attach to these cells and affect their 

activity. At any given time, dopamine molecules occupy 

some of the D2

 receptors, while the rest of the receptors remain available until a stimulus—such as drug 

exposure—increases dopamine levels. One hypothesis 

holds that the proportion of D2

 receptors a person has free 

affects how strongly he or she responds to the stimulus.

Imaging studies of the human brain have found reduced 

levels of available D2

 receptors among abusers of cocaine. 

But that work could not distinguish between pre-existing 

differences in the proportion of available receptors and 

changes induced by drug use. The human studies also 

showed reduced availability of D2

 receptors among abusers of heroin, nicotine, amphetamine, and alcohol. Lower 

D2

 receptor availability has also been observed in other 

populations, such as the severely obese. So, findings on 

D2

 receptor availability may be relevant to a wide range of 

addictions and conditions.

To measure monkeys’ D2

 receptor availability before 

cocaine exposure, Dr. Nader and colleagues injected each 

animal with a radiotracer that binds to the receptors. The 

radiotracer competes with dopamine for the receptor and 

provides a measure of D2

 function. Over the course of a 

3-hour brain imaging study, the scientists used positron 

emission tomography (PET) to visualize and quantify the 

bound radiotracer.

Next, the researchers allowed the monkeys to self-administer cocaine. Every day, they placed each monkey in an 

experimental chamber equipped with two levers—one 

that delivered banana pellets during the first 20 minutes 

of the test and another that provided the animal with an 

infusion of cocaine during the next 60 minutes. Then, 

the researchers put the animals through this sequence a 

second time. To describe the neurobiological effects of 

chronic cocaine exposure, the investigators continued the 

self-administration experiments and measured D2

 receptor 

availability for a year.

The monkeys whose PET scans had revealed lower D2

receptor availability at baseline testing before their initial 

cocaine exposure self-administered cocaine at higher rates. 

This finding suggests that lower D2

 receptor availability 

increases sensitivity to cocaine reward. Similar findings 

have been reported in studies that compared drug abusers and people who do not abuse drugs. The results also 

5
6

complement those of a prior study by 

Dr. Nader, which showed that subordinate monkeys, having lower D2

 receptor availability, self-administered more 

cocaine than dominant monkeys, which 

have higher D2

 receptor availability.

This finding suggests that 

lower D2

 receptor availability increases vulnerability 

to cocaine reward.

“This result, as well as findings of other 

studies, indicates that low D2

 receptor availability corresponds to increased vulnerability to 

cocaine abuse,” says Dr. Nader. “Perhaps an individual 

with low availability gets a greater kick from cocaine 

because the drug-induced dopamine release stimulates a 

greater percentage of their receptors. Another possibility 

is that the drug prompts some individuals’ brain cells to 

release dopamine in particularly high quantities that are 

sufficient to fill the great majority of vacant D2

 receptors, 

and this augments the high.”

Variable Recovery

PET scans obtained at intervals throughout the trial 

revealed a rapid and marked suppressive effect of cocaine 

on D2

 receptors. After 5 days of self-administration, the 

monkeys’ available receptors had dropped by 15 percent, 

on average. This effect was reversible: In three monkeys 

that were allowed to self-administer the drug for 1 week, 

D2

 receptor availability returned to baseline values by the 

third week of abstinence.

The picture was more complex, however, in five monkeys 

that self-administered cocaine for a year. At that time, 

D2

 receptor availability was down 22 percent (see graph). 

When access to cocaine was then stopped, three of the 

monkeys showed strong recovery—93 percent, on average—of receptor availability a month after cocaine cessation. But two monkeys had recovered only 80 percent and 

did not recover further over 12 months of abstinence.

Food Versus Drug

The researchers parsed the implications of the relationships between cocaine and D2

 receptors by comparing the 

monkeys’ patterns of lever pressing for the drug and for 

food. In contrast to the cocaine self-administration results, 

there was no correlation between D2

 receptor availability 

and how often monkeys pressed the food lever. This suggests that low D2

 receptor availability disposes individuals 

to seek the cocaine experience specifically, rather than 

rewarding experiences in general.

A clue to why recovery is more difficult for some individuals than others may come from the two monkeys whose D2

receptor availability failed to recover completely following 

year-long cocaine self-administration. Throughout the year 

of cocaine self-administration, these animals exhibited a 

reduced attraction to food, Dr. Nader says. When given 

the opportunity to press a lever for banana pellets, these 

animals did so only half as often as the monkeys whose 

receptors returned to baseline after long-term cocaine selfadministration. “Although the findings are preliminary, 

we believe that these individuals may find rewards other 

than cocaine devalued,” Nader says. “If it is not cocaine, it 

is just not rewarding to them.” That trait may presage an 

unusually long-lasting influence of the drug.

Toward Treatment

“Predisposition seems to play a role in addiction, as does 

the dopamine system’s rapid and robust reduction in D2

receptor availability in response to cocaine,” says 

Dr. Nader.

The team’s findings and those of others suggest that 

therapies that elevate D2

 receptor availability may help 

prevent and treat cocaine abuse. According to Dr. Nader, 

the medications that appear most likely to accomplish this 

without deleterious side effects do so indirectly by altering neurotransmitters other than dopamine—either by 

increasing serotonin or gamma aminobutyric acid. Dr. 

Nader and his colleagues plan to test this strategy in 

monkeys.

In prior research, Dr. Nader has shown that enriching 

individuals’ environments also can prompt the brain to 

generate additional D2

 receptors. “My colleagues and 

I are most intrigued by an environmental enrichment 

strategy for increasing D2

 receptor levels,” Dr. Nader 

says. “This approach is based on the most profound 

result that my colleagues and I have ever observed: Adult 

monkeys that have a high level of control over the social 

environment show enhanced D2

 receptor availability 

6
7

and markedly diminished response to cocaine’s rewarding effects” (see “Social Environment Appears Linked to 

Biological Changes in Dopamine System, May Influence 

Vulnerability to Cocaine Addiction”).

Other researchers have reported that, in rodents, environmental enrichment reverses the rewarding effects of 

cocaine. Dr. Nader and his team are preparing to test 

whether enhancing monkeys’ environments—for example, 

by reducing stress, providing novel objects, and increasing 

peer interaction—can increase receptor availability and 

curb cocaine self-administration.

If the enrichment is successful, analogous provisions for 

people—improved living conditions, broad recreational 

choices, stress management techniques, and rewarding 

activities—might reduce vulnerability to cocaine abuse.

“A question for further research is whether animals whose 

D2

 receptor availability levels remain low during abstinence are more likely to exhibit behaviors akin to relapse, 

compared with those whose receptors recover,” says Dr. 

Cora Lee Wetherington of NIDA’s Division of Basic 

Neuroscience and Behavioral Research. Dr. Nader says his 

team plans to adapt its current experimental protocol to 

explore this question in rhesus monkeys.

Sources

• Nader, M.A., et al. Positron emission tomography 

imaging studies of dopamine receptors in primate 

models of addiction. Philosophical Transactions of the 

Royal Society of London, Series B 363 (1507):3223-

3232, 2008. 

• Nader, M.A., and Czoty, P.W. Brain imaging in 

nonhuman primates: Insights into drug addiction. 

Institute for Laboratory Animal Research Journal 

49(1):89-102, 2008. 

• Nader, M.A., et al. PET imaging of dopamine D2

receptors during chronic cocaine self-administration 

in monkeys. Nature Neuroscience 9(8):1050-1056, 

2006. 
Research Findings

Volume #, Number (Month Year)

8

Aripiprazole Prevents Rats From Resuming Cocaine Seeking

A medication prescribed for schizophrenia and manic phases of bipolar disorder shows promise as a 

cocaine addiction treatment.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 22, Number 2 (December 2008)

The antipsychotic medication aripiprazole appears to 

reduce cocaine craving in small studies of addicted individuals with schizophrenia and bipolar disorder. A recent 

NIDA-funded experiment suggests that aripiprazole may 

help not only those very-difficult-to-treat individuals, but 

others as well, to maintain abstinence from the stimulant.

Drs. Ronald See and Matthew Feltenstein of the Medical 

University of South Carolina found that rats treated with 

aripiprazole were less likely than untreated rats to resume 

cocaine self-administration after a period of abstinence. 

The finding indicates that the medication reduces cocaine 

seeking directly rather than as a byproduct of altering psychotic symptoms or processes. Therefore, the researchers 

speculate, cocaine abusers who do not have concurrent 

psychotic illness may also benefit from aripiprazole.

Indifference to Cocaine With Few Side Effects

The researchers subjected rats to a protocol that simulates 

drug use, followed by the establishment of stable abstinence, and finally a test of the animals’ vulnerability to 

relapse. Animals that are vulnerable respond to a relapse 

trigger—a cocaine-associated cue or a priming dose of 

the drug—by pressing a lever they previously used to selfadminister the drug. The more vulnerable an animal is, 

the more often it will press the lever.

Rats given the lowest effective dose of aripiprazole (0.25 

mg/kg) before the priming dose of cocaine pressed the 

lever associated with cocaine 50 percent as often as control 

rats did. The higher the dose of aripiprazole, the less the 

rats responded to the relapse triggers. For example, after 

the drug trigger, rats given the highest dose of aripiprazole 

(15 mg/kg) pressed the lever associated with cocaine only 

9 percent as often as the rats receiving no aripiprazole.

To rule out the possibility that aripiprazole reduced the 

rats’ cocaine seeking through general effects—such as 

sedation or lethargy—that would be undesirable in a 

medication, the investigators conducted further trials that 

showed:

• Aripiprazole does not sedate animals to the point where 

they are too tired to approach and press levers for 

rewards. During the protocol that mimicked relapse, 

the lowest medication doses that attenuated lever 

pressing did not suppress locomotor activity. Higher 

doses (1 mg/kg and 5 mg/kg) reduced spontaneous 

and cocaine-induced locomotor activity only modestly. Furthermore, while aripiprazole-treated rats 

pressed the drug-linked lever less often, they continued to press another lever, which delivered nothing at 

all, as often as before.

• Aripiprazole does not make rats indifferent to rewards 

from all activities, including natural, healthy ones.

Aripiprazole did not reduce the enthusiasm with 

which rats pressed levers to obtain food, so it did not 

seem to blunt their natural pleasure responses. In 

addition, when the researchers put animals through a 

protocol that simulates ongoing drug use, rather than 

recovery from an addiction, the animals pressed levers 

to obtain cocaine infusions just as avidly after receiv8
9

ing aripiprazole as after saline. This result indicates 

that while the medication may help individuals maintain abstinence, it is unlikely to diminish ongoing 

binge cocaine abuse.

“Aripiprazole’s minimal effect on rats’ motor activity and 

other behaviors is consistent with its good safety profile 

and general acceptance among patients as a psychiatric 

medication,” says Dr. See. “We find it encouraging that 

low doses block drug seeking and seem to have no other 

discernible effects on the animals. Taken together, our 

findings suggest that aripiprazole may selectively reduce 

drug-seeking behavior and is a promising candidate medication for preventing cocaine relapse.”

A Selective Stabilizer

Dr. See and colleagues focused on aripiprazole for practical reasons: It is generally safe, it is already on the market, 

and its pharmacological action suggests the potential to 

reduce relapse. Aripiprazole preferentially binds to dopamine receptors D2 and D3, which are proteins on brain 

cell surfaces that mediate dopamine’s effects on cellular 

activity. The drug has different effects, depending on the 

amount of dopamine present. The overall effect is neurochemical modulation: Aripiprazole quiets hyperactive 

neurons and stimulates sluggish ones through both presynaptic and postsynaptic mechanisms, according to Dr. 

See. Such stabilization seems to account for the efficacy 

of aripiprazole as a psychiatric medication and may also 

underlie its benefit as a relapse-prevention agent.

“As a neurochemical stabilizer, aripiprazole most likely 

reduces excess dopamine activity in the mesolimbic reward 

circuit brought about by drug abuse,” says Dr. See. “The 

medication also may simultaneously boost dopamine in 

the cortex, particularly the prefrontal circuits, thereby 

enhancing the ability to suppress the desire for drugs.” 

Although aripiprazole also acts at serotonin receptors, 

pharmacologists currently consider dopamine stabilization 

to be its main therapeutic action.

To evaluate the full extent of aripiprazole’s promise, it 

must still be determined whether the medication could be 

used to treat addiction to other psychostimulants besides 

cocaine, notes Dr. Cora Lee Wetherington of NIDA’s 

Division of Basic Neuroscience and Behavioral Research. 

Dr. See notes that his team plans to perform animal tests 

of the drug’s effect on methamphetamine.

With regard to cocaine, Dr. Wetherington says, “the 

results of Dr. See’s animal study suggest that aripiprazole 

may help prevent relapse in cocaine abusers both with and 

without psychiatric conditions. The work lays the groundwork for future clinical research.”

Says Dr. See, “We hope to use brain imaging to examine 

aripiprazole’s effects on cocaine abusers’ responses to drug 

cues—to find out whether it dampens brain activity related to such cues. If so, that would also support the idea 

that the medication helps prevent relapse.”

Source

• Feltenstein, M.W., Altar, C.A., and See, R.E. 

Aripiprazole blocks reinstatement of cocaine seeking 

in an animal model of relapse. Biological Psychiatry

61(5):582-590, 2007. 
Research Findings

Volume 22, Number 2 (December 2008)

10

Long-Term Cocaine Self-Administration Depresses Brain Activity

Neural activity of monkeys diminishes in regions linked with cognition and emotion.

By Lori Whitten, NIDA Notes Staff Writer

Chronic exposure to cocaine depresses neural activity. 

Initially, the effect shows up mostly in the brain’s reward 

areas. With longer exposure, however, neural depression 

spreads to circuits that form cognitive and emotional 

memories and associations, according to NIDA-funded 

research by Drs. Thomas J.R. Beveridge and Linda J. 

Porrino and colleagues at the Wake Forest University 

School of Medicine.

Wider Effects With Longer Exposure

The researchers trained 14 male monkeys to press a lever 

for a reward. Six monkeys received banana-flavored food 

morsels, and eight received an infusion of cocaine (either 

0.03 mg/kg or 0.3 mg/kg). Each monkey received up to 

30 portions of food or infusions of cocaine daily for either 

5 or 100 days. The 100-day trial, much longer than most 

other studies of drug use in primates, closely mimicked 

chronic cocaine abuse among people. For monkeys in 

the high-dose group, each session ended when they selfadministered a dose equivalent to a person taking roughly 

0.5-1.0 gram of cocaine per day. The researchers estimate 

that their experiment models a person heavily abusing 

cocaine daily for roughly 1 year.

After each monkey’s final session, Dr. Porrino’s team 

mapped its rate of cerebral glucose metabolism—the 

primary indicator of cerebral energy expenditure. The 

researchers injected a radiolabeled form of glucose 

(2-[14C]deoxyglucose; 2-DG) and, using autoradiography, obtained images that showed how much fuel different brain areas were utilizing (see image). Greater glucose 

metabolism indicates greater neural activity.

All the monkeys that had self-administered cocaine showed 

some localized depression of glucose metabolism. In the 

monkeys that self-administered cocaine daily for just 5 

days, neural depression was largely restricted to pleasure and 

motivation areas, especially the reward circuit and areas that 

process expectations of rewards.

In the 100-day test, animals that had received the high 

dose of the drug revealed less neural activity in 40 of the 77 

brain regions analyzed as compared with animals that had 

received only food morsels (see table). The high-dose monkeys incurred a 16 percent drop, on average, in overall cerebral glucose metabolism. The low dose of cocaine depressed 

metabolism in 14 of the regions, but not overall.

The tests suggest that with 

longer exposure 

to cocaine, reductions in neural 

activity expand 

within and 

beyond the pleasure and motivation centers, 

says Dr. Porrino. 

“Within the 

structure called 

the striatum, 

the blunting of 

activity spreads 

from the nucleus 

accumbens, a 

reward area, to 

the caudateputamen, which 

controls behavior 

based on repetitive action,” she 

says. Long-term 

cocaine use also 

depressed memory and information-processing areas.

The findings accord well with those of human imaging 

studies, which have found general depression in cerebral 

blood flow among chronic cocaine abusers compared with 

nonabusers. By using animals, however, Dr. Porrino eliminated two sources of uncertainty in those clinical studies: differences in metabolic rates that may have predated 

cocaine abuse and abuse of drugs other than cocaine. “My 

team can directly attribute to cocaine the depressed brain 

metabolism observed in the study,” says Dr. Porrino.

“Our 100-day experimental protocol for rhesus monkeys 

gives a good picture of what might happen in the brains 

of cocaine abusers,” she says. “Some addiction researchers 

believe that the shift in activity within the striatum may, 

in part, underlie the progression from voluntary drug taking to addiction. Moreover, human imaging research has 

linked drug craving with the amygdala and insula, temporal lobe areas depressed by cocaine in our study.”
11

“The reduced activity of the temporal lobe indicates 

that this structure is somehow compromised,” says 

Dr. Nancy Pilotte of NIDA’s Division of Basic 

Neuroscience and Behavioral Research. “Some of 

these regions mediate the ability to connect emotionally, and cocaine’s blunting of them may induce 

a flattened affect similar to depression symptoms 

that are common among chronic cocaine abusers.”

“Dr. Porrino and her colleagues have identified key 

brain structures affected by long-term cocaine exposure and have provided a valuable set of observations 

that could serve as a basis for future research,” Dr. 

Pilotte says. For example, she adds, researchers might 

now focus on those regions when gauging the effectiveness of potential medications for cocaine addiction or when measuring recovery after abstinence.

Sources

• Beveridge, T.J.R., et al. Chronic cocaine selfadministration is associated with altered functional activity in the temporal lobes of nonhuman primates. European Journal of Neuroscience

23(11):3109-3118, 2006.

• Porrino, L.J., et al. The effects of cocaine: A 

shifting target over the course of addiction. 

Progress in Neuropsychopharmacology and 

Biological Psychiatry 31(8):1593-1600, 2007. 

11
Methadone Reduces Rats’ Cocaine Seeking

High-dose methadone undermines animals’ motivation to acquire cocaine.

By NIDA Notes Staff

Research Findings

Volume 22, Number 2 (December 2008))

Methadone may prove to be an effective treatment for 

cocaine as well as opioid abuse, if the results of a recent 

study with rats, funded by NIDA and the Canadian 

Institutes of Health Research, can be replicated and 

applied to people. The animals’ cocaine seeking dropped 

in response to methadone given in doses that produce 

blood levels equivalent to those therapeutically effective 

for opioid addiction. Methadone at more than twice that 

dose abolished cocaine seeking.

“Methadone is the primary drug used to treat opiate 

dependence worldwide, yet there is still so much to find 

out about it,” says Dr. Francesco Leri of the University 

of Guelph in Ontario, Canada. “My colleagues and I are 

exploring the effects of maintaining relatively stable doses 

of methadone over time in rats to discover all of the benefits and properties of this valuable medication.”

Extinguising Rats’ Motivation

Clinical trials have shown that people who take high-dose 

methadone for 

heroin addiction and who are 

also addicted to 

cocaine decrease 

their abuse of 

both drugs. 

To Dr. Leri, 

that observation suggested 

that methadone 

might have 

unexploited 

potential as a 

medication to 

treat cocaine 

abuse in patients 

both with and 

without histories 

of opioid abuse. 

Accordingly, 

with colleagues 

at Concordia 

University in 

Montreal and 

Rockefeller University in New York, Dr. Leri set out to 

better understand methadone’s effect on cocaine seeking.

The team first tested whether methadone would suppress 

the normal tendency of rats to seek cocaine once they 

have been repeatedly exposed to the stimulant. To prepare 

their animals for the test, the researchers put some on 

methadone (20 or 55 mg/kg/day) via implanted minipumps and gave others saline by the same route. During 

these regimens, for 2 weeks, the researchers trained the 

animals to associate one designated chamber with cocaine 

injections and another with saline injections. Daily for 

3 days, they injected each animal once with cocaine (1, 

5, or 20 mg/kg) and once with saline. Immediately after 

each cocaine injection, they placed the animal in the first 

chamber; after each saline injection, they placed it in the 

second chamber.

On the day of the test, the researchers placed each rat 

between the two chambers without giving it any cocaine 

or saline, and monitored where it went. Among the 

animals given the highest dose of cocaine, those that 

received no methadone showed a strong preference for 

the cocaine-associated chamber; those that received the 

lower methadone dose showed less preference; and those 

maintained on the higher methadone dose, no preference 

at all, indicating a total loss of motivation to seek cocaine 

(see graph).

Another experiment by Dr. Leri’s team assessed methadone’s impact on cocaine seeking by measuring how hard 

rats will work to obtain the drug intravenously. They first 

trained rats to press a lever for cocaine, then implanted 

mini-pumps: Eight animals received 30 mg/kg/day of 

methadone, while another six received only saline. The 

12

“Overall, our results support the usefulness of high-dose methadone as a 

pharmacological tool to reduce severe 

cocaine abuse in opioid-dependent 

individuals.”-Dr. Francesco Leri
rats were allowed to self-administer cocaine, but the system was programmed to require progressively more presses 

before it would release each successive infusion. The eight 

methadone-treated animals gave up pressing the cocaine 

lever after six presses, on average, whereas the rats that did 

not receive methadone continued to press it more than 30 

times to receive a single dose (see graph).

Some scientists have suggested that methadone-induced 

sluggishness saps individuals’ initiative to seek cocaine. 

But Dr. Leri asserts that other behavioral tests by his team 

rule out this explanation. For example, methadone did not 

alter the animals’ general activity, food consumption, or 

response to heat-generated pain.

“Overall, our results support the usefulness of high-dose 

methadone as a pharmacological tool to reduce severe 

cocaine abuse in opioid-dependent individuals and possibly in the management of addiction to only cocaine,” Dr. 

Leri says.

Although the study found high-dose methadone to be 

effective in this regard, the highest doses of methadone 

tested in rats produced blood concentrations of the drug 

more than twice as high as those achieved in people 

undergoing standard methadone therapy. “To determine whether higher levels of methadone can be efficacious without producing adverse effects, we need clinical 

research on doses that are higher than customarily used in 

drug abusers,” says Dr. Nancy Pilotte, of NIDA’s Division 

of Basic Neuroscience and Behavioral Research.

Brain Correlates

Methadone helps heroin abusers abstain from opioids by 

partially stimulating the brain’s mu-opioid receptors, an 

effect that keeps the symptoms of withdrawal at bay and 

also blocks the rewarding effects of other opioids. But it 

is not clear how methadone suppresses cocaine seeking. 

Methadone does not, for example, directly interact with 

the dopamine transporter, the brain protein that is primarily responsible for the cocaine high.

Dr. Leri suspects that the mu-opioid receptor, which 

is the site where methadone exerts its primary activity 

against opioid addiction, also plays a role in the medication’s potentially therapeutic effect on cocaine addiction. 

In support of this idea, he and collaborators at Rockefeller 

University in New York City showed that cocaine increases production of the mu-opioid receptor in the nucleus 

accumbens, a key brain area involved in reward and 

addiction. Methadone, they also found, counteracts these 

increases.

In the experiments, rats exposed to three injections of 5 

or 20 mg/kg doses of cocaine were found to have more 

mu-opioid receptor messenger RNA (mRNA)—an indicator of receptor production rates—than animals exposed 

to three injected doses of the drug at 1 mg/kg. These 

elevations were less pronounced, however, in rats that 

were being maintained on 20 mg/day of methadone at 

the time of the cocaine exposures. Moreover, rats exposed 

to cocaine while being maintained on 55 mg/kg/day of 

methadone had mu-opioid mRNA levels that were indistinguishable from those of rats that received no cocaine.

From these results, the researchers hypothesize that 

methadone probably blocks cocaine seeking by inhibiting cocaine-induced enhancement of muopioid receptor 

production. Other explanations may be possible, however, 

as enhancing receptor production is not methadone’s only 

effect on brain chemistry. Among its other influences, it 

boosts the body’s natural opioids, the endorphins. Dr. 

Mary Jeanne Kreek of Rockefeller University says, “We 

wonder whether people who are dependent on both 

heroin and cocaine respond well to methadone because 

methadone reduces the number of mu-opioid receptors in 

the reward system of their brains or whether they respond 

because cocaine depletes endorphins and methadone 

brings the endorphins back.”

“Methadone and the mu-opioid antagonist, naltrexone, 

which blocks the mu receptor and its associated responses, 

can both be considered as treatments for cocaine abuse, as 

both decrease the availability of the mu-opiate receptor,” 

says Dr. Pilotte. “Methadone may even be the better treatment as it does not force the client into an uncomfortable 

state of withdrawal as it decreases the incentive to take 

cocaine.”

13
Sources

• Leri, F., et al. High-dose methadone maintenance 

in rats: Effects on cocaine self-administration and 

behavioral side effects. Neuropsychopharmacology

32(11):2290-2300, 2007.

• Leri, F., et al. Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine selfadministration, and mu-opioid receptor mRNA expression in the rat brain. Neuropsychopharmacology 

31(7):1462-1474, 2006. 

14
15

Brain Proteins Differ in Cocaine-Overdose Victims

Research Findings

Volume 22, Number 2 (December 2008)

Scientists have found differences in protein concentrations in the brain pleasure centers of 10 people who died from 

cocaine overdose as compared with 10 people who did not abuse the drug. Dr. Scott Hemby and colleagues at Wake 

Forest University and the University of Miami Schools of Medicine used mass spectrometry to measure more than 1,400 

proteins in post-mortem tissue samples from the nucleus accumbens. Levels of roughly 50 proteins were found to be 

either higher or lower in the cocaine abusers. These proteins participate in basic neurobiological processes such as forming cellular structures, strengthening neuronal connections, sending chemical messages between cells, deriving energy 

from glucose, and protecting cells from injury. Such information may point scientists toward new insights into the 

molecular mechanisms and consequences of cocaine addiction.

Source

• Molecular Psychiatry 12(1):55-73, 2007. 
Research Findings

Volume #, Number (Month Year)

16

Fewer Young Adults Abuse Cocaine and Methamphetamine, 

National Survey Finds

Volume 22, Number 2 (December 2008)

The percentage of young adults who said they were abusing cocaine or methamphetamine dropped substantially 

from 2006 to 2007, according to the 2007 National 

Survey on Drug Use and Health (NSDUH), published in 

September 2008. Overall drug abuse, however, remained 

constant: According to the survey, an estimated 19.9 million Americans age 12 and over used an illicit drug in the 

previous month. That rate has held steady since 2002.

As in past years, young adults (aged 18-25) reported the 

highest rates of substance abuse. About 20 percent said 

they abused one or more illicit drugs; 16.4 percent said 

they abused marijuana, which topped the list of abused 

drugs in this cohort. Abuse rates for marijuana and most 

of the other drugs have changed little in the past 6 years. 

However, the decline in abuse of the stimulants cocaine 

and methamphetamine in this group runs counter to that 

pattern. In 2007, for example, 1.7 percent of the young 

adults reported cocaine abuse, a 23 percent decline from 

the previous year. Methamphetamine abuse in this age 

group dropped by a third, to 0.4 percent.

By contrast, 12- to 17-year-olds have reported a steady 

decline in overall illicit drug use, from 11.6 percent in 

2002 to 9.5 percent in 2007. Driving the decline in 

this cohort has been an 18 percent drop in marijuana 

use, from 8.2 percent in 2002 to 6.7 percent in 2007. 

Inhalants are the only drug category that showed no 

decline among adolescents over that 6-year period, 

although rates for some drugs have leveled off since 2005.

Rates of drug abuse tend to decline steadily after the age 

of 25. However, as more baby boomers (people born 

between 1946 and 1964) enter the 50-59 age range, 

illicit drug use in that group has risen, jumping from 2.7 

percent in 2002 to 5 percent in 2007. “Illicit drug use 

has historically been more prevalent in the baby boomer 

cohort. As its members age into the 50-59 age category, 

the prevalence increases relative to prior cohorts in this 

age group,” says Dr. Marsha Lopez of NIDA’s Division of 

Epidemiology, Services and Prevention Research.

Marijuana remains the most commonly used illicit drug 

across the survey, with an estimated 14.4 million pastmonth users. In 2007, roughly 2.1 million people smoked 

marijuana for the first time, and a similar number started 

using prescription painkillers for nonmedical purposes; 

these drugs drew more initiates last year than any other. 

Of the estimated 6.9 million people who used prescription 

psychotherapeutic drugs nonmedically, 5.2 million chose 

painkillers, representing a 16 percent rise in nonmedical use of these drugs since 2004. On a positive note, the 

2007 survey found a significant 1-year decline in the nonmedical use of prescribed stimulants.

In 2007, as in previous years, men reported higher rates of 

past-month illicit drug use than women (10.4 percent versus 5.8 percent). Among ethnic groups, American Indians/

Alaska natives had the highest rate of illicit drug use (12.6 

percent) of any racial/ethnic group, followed by multiracial individuals (11.8 percent), African-Americans (9.5 

percent), whites (8.2 percent), Hispanics (6.6 percent), 

and Asians (4.2 percent). No group had a significant 

change from the previous year.

The trends determined by NSDUH for adolescents and 

young adults are generally consistent with those reported 

by the NIDA-funded Monitoring the Future survey. 

16
17

(For more information, see NIDA Notes, Volume 21, 

Number 5, March 2008, page 15). The survey, based on 

the responses of 67,500 participants, is available online at 

www.oas.samhsa.gov/NSDUHlatest.htm. Hard copies can 

be ordered free by calling (800) 729-6686.

Source

• Substance Abuse and Mental Health Services 

Administration, 2008. Results from the 2007 

National Survey on Drug Use and Health: National 

Findings (Office of Applied Studies, DHHS 

Publication No. SMA 08-4343). Rockville, MD: 

SAMHSA. 

17
Research Findings

Volume #, Number (Month Year)

18

Mice With Genetic Alteration Eschew Cocaine

A South American caterpillar inspired a successful 10-year quest to desensitize the dopamine 

transporter to the drug.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 6 (June 2008)

NIDA researchers have desensitized mice to cocaine by 

genetically altering their dopamine transporters—proteins 

that are a key target of cocaine—to resemble ones found 

in the brains of some insects. If investigators can identify a 

compound that alters these transporters in the same manner, they might be one step closer to developing medications to treat cocaine addiction.

A South American caterpillar started the researchers on their 

path to the discovery. Larvae of the Eloria noyesi moth have 

a particular appetite for leaves of the coca plant. This preference has captured the interest of drug-control authorities, 

who view the caterpillar as a potential tool for eradication 

of coca crops. To Dr. Howard Gu at Ohio State University 

(OSU), however, the caterpillar’s apparent immunity to 

the psychoactive properties of the coca leaf suggested something else: Perhaps cocaine’s target protein in the caterpillar’s brain—the dopamine transporter (DAT)—does not 

respond to the leaf. If so, he reasoned, an understanding of 

how the insect’s DAT functions might provide a template 

for pharmacological agents to block the effects of the coca 

leaf’s potent derivative, cocaine.

Scientists generally believe that cocaine produces its high by 

preventing DATs from regulating dopamine levels in the 

brain’s reward system, resulting in a euphoria-producing 

buildup of the neurotransmitter in the nucleus accumbens 

(NAc). If an animal reliant on coca for nutrition were to 

be subject to this effect, however, surges of euphoria would 

occur whenever it ate and presumably be very disruptive 

of its functioning. “Because the caterpillar is interested in 

coca leaves as a food source, we hypothesized that its DATs 

might not interact with cocaine,” Dr. Gu says.

A Surprising Twist

Dr. Gu undertook a 10-year project that ultimately established a mutated form of DAT that is cocaine-insensitive. 

But he encountered several surprising twists—and frustrating letdowns—along the way.

Chief among these, Dr. Gu was disappointed to find that 

the DAT from Eloria is not substantially less sensitive to 

cocaine than the DAT from other insects they tested, such 

as a silkworm that does not eat coca leaves. He quickly 

recognized that there was nothing unique about the Eloria 

caterpillar in this regard and was forced by that evidence 

to relinquish the elegant evolutionary theory he had held 

about how its insensitivity to the stimulating effects of the 

coca leaf might have developed.

But what he learned in the process was more important 

than a busted theory: Dr. Gu discovered that the DATs 

from a number of insect species are just 5 percent as sensitive to cocaine as is mouse DAT. “I seized on the difference to generate clues about how to alter the mouse DAT 

to be cocaine-insensitive like the insects’,” he says.

As a first step, Dr. Gu switched fragments of insect DAT 

sequences with mouse DAT sequences and identified key 

regions that affect how tightly cocaine binds to the DAT 

protein. He then randomly generated a large number of 

alterations in these regions of the mouse DAT sequence. 

Working with cultured cells, he tested them one by one 

to see if the changes they introduced would desensitize 

mouse DAT to cocaine. Through this laborious process, 

he eventually identified the sequence changes that make 

the transporter cocaine-resistant.

Dr. Gu created mutant mice with the same DAT 

sequence changes. The mutant mice produced cocaineresistant DAT. But were the animals truly immune to the 

rewarding sensations of the drug? Dr. Gu joined with 

colleagues at OSU and the University of Tennessee 

18
19

College of Medicine to answer this 

question.

Selective Indifferene

When normal mice are exposed to 

cocaine in one compartment of a split 

cage, they demonstrate liking for the 

drug by later spending the bulk of their 

time in that compartment. The proportion of time the animals spend in the 

drug-associated compartment provides 

a quantitative behavioral measure of 

the intensity of the drug’s rewarding 

effects. In Dr. Gu’s trials, the mutant 

mice spent no more time in a cage area 

where they received the injections of 

cocaine (5 mg/kg or 20 mg/kg) than 

they did in a compartment where they 

were given saline injections—a clear 

demonstration that they were not experiencing cocaine’s rewarding effects 

(see graph, left panel).

To ensure that the mutant mice 

retained normal responses to stimuli other than cocaine, 

the researchers gave them amphetamine. This stimulant 

triggers dopamine surges by mechanisms different from 

those that cocaine triggers. The researchers found that 

both mutant and normal mice developed elevated extracellular dopamine in the NAc after amphetamine exposure. 

In addition, the mutants exhibited as much behavioral 

evidence of amphetamine reward as did a comparison 

group of normal mice (see graph, right panel).

“The mutants’ response to amphetamine demonstrated 

that the neural machinery works properly in these animals, and they are not generally deficient in drug-induced 

reward,” says Dr. Gu.

Dr. Gu’s team is now seeking to identify a chemical 

compound that will prevent human DATs—like the 

mouse’s altered DAT—from responding to cocaine. Such 

a compound would eliminate the drug high and limit the 

frequency and length of relapses. Yet it would not interfere with the DAT’s ability to regulate dopamine, which 

produces feelings of reward and motivation vital for lifepromoting activities, such as eating. NIDA is supporting 

research to screen for such compounds with a protocol 

and cell lines provided by Dr. Gu.

A Theory Bolstered

Beyond yielding leads for medication development, Dr. 

Gu’s findings alleviate doubts that have arisen about the 

strategy of selective DAT desensitization to reduce cocaine 

reward. In some studies, animals continued to exhibit dopamine surges and behavioral responses to cocaine despite 

having been genetically altered to lack DAT.

“The results from mice without DAT represented a milestone in cocaine research—it was remarkable that these 

mice still experienced a high from cocaine,” explains Dr. 

Gu. “In view of that observation, it is reasonable to question the approach of finding compounds that prevent 

cocaine from binding to the DAT as a therapeutic strategy 

for cocaine abuse. The results from our mutant mice, however, indicate that DAT altering can block cocaine reward.”

In light of their work with the mutants, the researchers now 

attribute the persistence of cocaine response in DAT-less 

mice to adaptation. “The brains of DAT knock-out mice 

seem to undergo significant adaptive neurobiological changes that alter how cocaine produces its effects,” says Dr. Gu.

“Dr. Gu and colleagues have verified decisively that 

cocaine’s inhibition of DAT is necessary for its behavioral 

effects, answering an important question in addiction 

research,” says Dr. Nancy Pilotte of NIDA’s Division of 

Basic Neuroscience and Behavioral Research. She notes, 

however, that the strong confirmation of DAT’s role in 

cocaine reward does not rule out the idea of redundant 

systems. “If the dopamine system is damaged, as it is in 

the DAT-less mice, the brain may ‘train’ norepinephrine 

and serotonin neurons to take over reward and other functions,” she says.

Source

• Chen, R., et al. Abolished cocaine reward in mice 

with a cocaine-insensitive dopamine transporter. 

Proceedings of the National Academy of Sciences

103(24):9333-9338, 2006. 

19
Research Findings

Volume #, Number (Month Year)

20

Long-Term Cocaine Abuse Linked With Impaired Heart Function

Cocaine Can Mobilize Stored Dopamine

Volume 21, Number 5 (March 2008)

Long-term regular cocaine abuse impairs cardiac left ventricular function in AfricanAmericans, say NIDA-funded researchers Dr. Shenghan Lai and colleagues at The Johns 

Hopkins Medical Institutions. Magnetic resonance imaging of heart muscle contractions 

disclosed lower pumping efficiency in areas of the left ventricular wall among 32 AfricanAmericans who abused cocaine compared with 14 nonabusers. The study participants, 

men and women aged 25 to 54, were all in good health with no signs of heart disease; the 

findings suggest that prolonged exposure to the drug may cause subclinical impairment 

that increases risk for cardiac events. Acute cocaine abuse has previously been associated 

with several cardiac complications, including arrhythmia, ruptured aorta, heart attack, 

and sudden death.

Source

•	 American Journal of Cardiology 97(7):1085-1088, 2006. 

Cocaine increases dopamine levels primarily by preventing the neurochemical from being transported back into 

its releasing cell, leaving more outside the neuron, where it contributes to the drug’s euphoric effects. Dr. R. Mark 

Wightman and colleagues of the University of North Carolina at Chapel Hill and Dr. George Augustine of Duke 

University have recently shown that cocaine also can tap into an intracellular dopamine reserve pool. As far back as the 

1970s, some researchers suspected this could occur, but they could not confirm it. Now, thanks to advances in molecular genetics and techniques to study neurotransmission, scientists have learned in studies with mice that proteins called 

synapsins, under the control of three genes, lock up the reserve pool by tethering its vesicles to the neuron’s internal 

structural framework. When the cell is called upon to release extraordinary amounts of the neurotransmitter, a chemical reaction relaxes the synapsin’s grasp on reserve pool vesicles, allowing them to join the releasable pool. “Although 

this extra mechanism is definitely not the most important action of cocaine, it points to a way that the drug can switch 

dopamine cells into a sustained-release mode, promoting the activation that dopamine exerts on its target neurons,” 

says Dr. Wightman.

Source

•	 The Journal of Neuroscience 26(12):3206-3209, 2006. 

20
Chronic Cocaine Abusers Have Occult Insomnia in Early Abstinence

Patients in early treatment may not recognize their own sleep impairment or its impact on their performance.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 5 (March 2008)

Chronic cocaine abusers may feel they are sleeping better 

and better during early abstinence, but objective measures 

show the opposite happens. A team of NIDA-funded 

addiction and sleep researchers at the Yale and Harvard 

Schools of Medicine found evidence of insomnia, with 

learning and attentional deficits, on days of taking the 

drug and after 2.5 weeks of abstinence. The researchers 

believe cocaine may impair the brain’s ability to gauge its 

own need for sleep, and patients’ ability to benefit from 

early treatment may suffer as a result.

“Problems in memory and attention are linked with 

increased treatment dropout and likely affect patients’ 

ability to ‘take in’ lessons from drug 

abuse counseling,” says Dr. Robert 

Malison of Yale, a co-investigator on 

the study. If the results are confirmed, 

clinicians and patients may want to 

consider addressing sleep disorders in 

early therapy, perhaps with the use of 

medications or behavioral treatments.

The researchers recruited 10 men 

and two women aged 24 to 49 who, 

on average, had abused cocaine for 

17 years and had used $500 worth 

of the drug per week. All the participants declined an offer of drug abuse 

treatment. Urine tests indicated that 

cocaine was the only drug any of them 

had abused during the week before 

the study.

At the outset of the study, participants 

self-administered cocaine from a pump 

under physician oversight, building up 

to a dose of 32 mg/kg of body weight 

over 1.5 hours, then repeating this dose 

essentially at will, but no less than 5 

minutes apart, for another 1.5 hours. 

Subsequently, they self-administered 

the higher dose with the same minimal restriction for 2 hours on each of 

three consecutive days, either on days 

4-6 or 18-20. This schedule simulated 

chronic cocaine abusers’ typical bingeing pattern of drug abuse and allowed 

researchers to monitor each participant’s sleep and cognitive performance for 17 days after a binge.

Research staff made sure the participants stayed awake 

from 7:45 AM to 9:30 PM, and let them sleep through 

the night. At night, the participants wore Nightcap sleep 

monitors, a bandana-like device that records eye and 

body movements that indicate whether someone is awake, 

asleep and dreaming, or sleeping dreamlessly. On most 

nights participants also wore polysomnographic (PSG) 

devices that continuously assessed brain activity with 

electroencephalography (EEG) and measured eye and 

muscle movements associated with different sleep stages. 

21
measures, relative to healthy, agematched peers who participated 

in prior studies. For example, 

they had less total sleep time 

(336 versus 421-464 minutes) 

and took longer to fall asleep 

(19 versus 6-16 minutes).

• Declines in sleep quantity and 

quality—The time participants 

took to fall asleep and their total 

time asleep transiently improved 

during the first week of abstinence, but then reverted to the 

patterns recorded on days of 

cocaine taking. On abstinence 

days 14-17, participants took 

an average of 20 minutes to fall 

asleep (from a low of 11) and 

slept for 40 minutes less than 

their minimum. Slow-wave 

sleep—a deep sleep that often 

increases following sleep deprivation—rose during the binge and 

on abstinence days 10-17.

• Lack of awareness of their sleep 

problems—In contrast to the 

evidence of objective measures, 

the study participants reported 

steadily improving sleep from 

the beginning to the end of their 

days of abstinence.

• Impairments in learning and 

attention—As with sleep quality, participants’ performance on 

tests of alertness and motor-skills 

learning initially improved and 

then deteriorated. On abstinence 

day 17, they registered their lowest scores on alertness and ability 

to learn a new motor skill.

Increased Risk of Relapse

“Unlike most people with chronic 

insomnia, including alcoholics, 

cocaine abusers do not perceive sleep 

problems and may not ask clinicians 

for treatment to improve sleep,” says 

Dr. Malison. The problem often goes 

unaddressed and persists as a result, 

and the accompanying impairments 

in attention and learning may affect 

how well they respond to drug abuse 

treatment (see “Cocaine Abusers’ 

Cognitive Deficits Compromise 

Treatment Outcomes”). Clinical 

studies have shown that poor objective sleep during the first 2 weeks of 

abstinence predicts relapse to alcohol 

5 months after treatment.

In fact, the insidious nature of 

cocaine-related insomnia may directly 

trigger relapse, suggests Dr. Peter 

Morgan, lead investigator of the 

study. “Addicted people may take 

cocaine to improve sleep-related cognitive functioning deficits—unaware 

that they are abusing, in part, to 

‘solve’ these problems.”

Dr. Morgan adds, “Cocaine abusers 

who recognize their cognitive problems often report that it takes them 6 

months to a year to turn the corner—

a clinical observation that points to 

the need for longer term studies of 

sleep and treatment outcomes among 

this population.” In addition to studies with larger numbers of participants, the investigators say there is a 

need to investigate possible gender 

differences in cocaine-related sleep 

problems. Dr. Morgan and his team 

are currently testing two medications, 

tiagabine and modafinil, to see if they 

can improve cocaine abusers’ sleep 

and restore cognitive performance.

“Experts believe that not getting 

enough sleep is an unmet public health problem in the general 

population. These findings highlight this important problem in 

cocaine abusers,” says Dr. Harold 

Gordon of NIDA’s Division of 

Clinical Neuroscience and Behavioral 

Research.

Source

• Morgan, P.T., et al. Sleep, sleepdependent procedural learning 

and vigilance in chronic cocaine 

users: Evidence for occult insomnia. Drug and Alcohol Dependence

82(3):238-249, 2006. 

22

Combining the information gathered 

by these measures with participants’ 

responses to daily questionnaires on 

their sleep experience and with cognitive testing, the researchers demonstrated that the participants had:

• Sleep deficits—After 14 to 17 days 

of abstinence, the study group 

exhibited sleep deficits on several 
Neuropeptide Promotes Drug-Seeking and Craving in Rats 

Orexin emerges as a link in the chain of brain mechanisms regulating appetite for rewards.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 4 (October 2007)

Orexin, a neuropeptide that stimulates eating and 

regulates wakefulness, also fosters animals’ drug seeking and craving responses to drugs, according to two 

NIDA-funded studies. The research teams, led by Drs. 

Glenda Harris and Gary Aston-Jones at the University of 

Pennsylvania and Drs. Stephanie Borgland and Antonello 

Bonci at the University of California, San Francisco 

(UCSF), used different experimental procedures and studied different drugs. Their findings, however, point to the 

same conclusion: Augmenting orexin increases drug seeking, while blocking it has the opposite effect.

Orexin, also called hypocretin, is produced by neurons in 

the hypothalamus—a brain structure that regulates hunger, thirst, sleep, and other processes essential to survival. 

Scientists recently discovered that people with narcolepsy 

lack orexin-producing neurons. The finding suggested an 

explanation for a striking observation made in the mid1970s: People with narcolepsy rarely became addicted 

to the potent stimulants used to treat the disorder at the 

time. Perhaps, some scientists speculated, orexin contributes to the development of drug abuse.

Orexin and Drug Seeking

An observation in animals by Drs. Harris and Aston-Jones 

also seemed to suggest a possible connection. They noted 

that lateral hypothalamus (LH) cells in the same area as 

orexin neurons were activated during drug seeking using a 

behavioral assay called conditioned place preference (CPP; 

for more on CPP, see “Animal Experiments in Addiction 

Science”). After repeated morphine injections in one 

chamber of a test cage and saline in the other, rats gravitate to the drugpaired area in an effort to re-experience 

the opiate effects. The time they spend in the area—their 

morphine place preference—indicates how intensely 

the drug motivates drug seeking. When Drs. Harris and 

Aston-Jones determined that the LH neurons activated 

during drug seeking produce orexin, they conducted further experiments.

The Pennsylvania researchers first demonstrated that activation of orexin neurons in the LH was tightly coupled 

with rats’ place preferences for morphine, cocaine, and 

sweet food. Next, they gave a different group of rats 

morphine for 3 days to establish place preference, then 

stopped the drug and injected some rats with a compound 

(SB334867) that prevents orexin from interacting with 

brain cells. Following treatment with SB334867, rats 

spent 58 percent less time in the morphine-associated 

cage area—indicating a halving of their drug seeking. 

Rats given inert vehicle showed no significant change 

in drug seeking.

The investigators also tested orexin’s impact on the tendency of a new group of rats to revert to drug seeking 

after CPP waned following extended testing without drug 

administration (extinction). In contrast to the first experiment, this time the investigators injected a compound 

(rat pancreatic polypeptide, rPP) that stimulates orexin 

neurons into the LH of some animals. These rats quickly 

resumed CPP—indicated by the difference in time spent 

in the morphine versus saline chambers—as marked as 

that of another group that received a morphine priming 

injection (353 seconds and 424 seconds for rPP and morphine, respectively). Rats that received a vehicle injection 

did not renew morphine CPP.

To establish that stimulation of orexin neurons by rPP, 

and not some other unidentified factor, was responsible 

for the effects in their second experiment, the investigators repeated the procedure. This time they blocked the 

extinction of orexin by giving the rats SB334867 prior to 

rPP. These rats did not resume CPP. Finally, the researchers infused orexin directly into rats’ ventral tegmental area 

(VTA), the origin of the dopamine-rich reward pathway, 

and observed a resumption of drug-seeking behavior.

23
24

Drugs May Unsurp Feeding System

The results, although in animals, suggest that orexin 

promotes drug abusers’ desire for drugs and their risk for 

relapse. “It makes sense, anatomically and physiologically, 

that orexin might play a role in reward-seeking and craving,” says Dr. Harris, now at the Centre de Regulacio 

Genomica in Spain. “Neurons in this part of the brain 

stimulate eating; intense cravings for food and water 

originate here. Our findings suggest that orexin from the 

lateral hypothalamus affects the reward pathway. Perhaps 

drugs take over the brain system for feeding and craving 

just as they usurp neural systems for reward.”

“These behavioral findings extend the team’s important 

anatomical work differentiating two populations of orexin-producing neurons in the hypothalamus. One population, located in the lateral hypothalamus, is involved 

in feeding, reward, and drug seeking, while the other 

regulates sleep and arousal,” says Dr. Susan Volman of 

NIDA’s Division of Basic Neuroscience and Behavioral 

Research. “The findings identify new neural pathways 

involved in drug abuse, craving, and relapse, and may ultimately help scientists find more effective therapies.

A Role in Cocaine Craving?

Drs. Borgland and Bonci and colleagues at the UCSF 

Ernest Gallo Clinic and Research Center demonstrated 

orexin effects on cocaine-related behaviors remarkably 

consistent with those the Pennsylvania team showed with 

respect to drug-related behaviors. They also provided 

evidence that orexin produces these effects at least in part 

by altering neurons in the VTA. The UCSF team used 

behavioral sensitization to evaluate orexin’s impact on rats’ 

responses to cocaine. Scientists generally think animals’ 

behavioral sensitization—increased locomotor activity following repeated exposure to a drug—reflects drug-induced 

neural changes and corresponds to human craving for 

the drug. In the UCSF experiment, rats pretreated with 

an orexin blocker displayed only half as much increase 

in locomotor activity (138 percent) following five daily 

cocaine infusions (15 mg/kg) as rats pretreated with an 

inert vehicle (257 percent).

To explore the cellular bases for their behavioral observations, the UCSF group measured orexin’s effects on the 

electrophysiological properties of dopamine-producing 

cells in brain slices removed from the VTA of rats. The 

results showed that orexin increased the number of receptors for neural excitation on the surfaces of these cells. 

Such strengthening of intercellular connections occurs 

during learning. Scientists believe it may foster the development of drug craving. When the researchers pretreated 

the rats with an orexin blocker, cocaine lost its ability to 

alter dopamine-producing cells in the VTA, suggesting 

that orexin may be necessary for cocaine-induced neuroplasticity and its behavioral consequences.

“Our findings point to a key role for orexin in the neural 

changes in the reward pathway that underlie craving and 

relapse,” says Dr. Borgland. “The physiological alterations 

we observed likely influence those cells’ dopamine release, 

perhaps affecting the activity of the reward pathway in a 

way that increases the likelihood of relapse. One implication of our findings is that addiction medication development efforts might do well to target orexin receptors,” 

she says. The work of the Pennsylvania and UCSF teams 

points to orexin involvement in reward-seeking in general. 

Researchers studying the effects of orexin-blocking compounds in animal models of alcoholism and obesity have 

reported preliminary but promising findings. Both teams 

are currently determining whether giving such compounds 

to animals reduces self-administration of cocaine, say Dr. 

Bonci and Dr. Aston-Jones, the latter now at the Medical 

University of South Carolina.

Sources

• Harris, G.C., Wimmer, M., and Aston-Jones, G. A 

role for lateral hypothalamic orexin neurons in reward 

seeking. Nature 437(7058):556-559, 2005. 

• Borgland, S.L., et al. Orexin A in the VTA is critical 

for the induction of synaptic plasticity and behavioral 

sensitization to cocaine. Neuron 49(4):589-601, 

2006. 

24
Gene Experiment Confirms a Suspected Cocaine Action 

Building on knowledge from developmental and cancer biology, addiction researchers are learning how 

acute and chronic cocaine exposure regulates certain genes.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 4 (October 2007)

Cocaine produces the long-term brain changes 

that underlie addiction in part by activating certain genes. Dr. Eric Nestler and colleagues at the 

University of Texas Southwestern Medical Center 

and Harvard Medical School have shown that 

the drug achieves this activation at least in part 

through a process called chromatin remodeling.

The finding opens up a new avenue for potential 

therapies for addiction. “Our research suggests 

that testing chemical compounds that reverse 

chromatin remodeling is a promising approach to 

seeking treatments for drug abuse. This is already 

a major strategy for cancer therapy development,” 

says Dr. Nestler.

Genes Regulate Crucial Proteins

Cocaine activates the genes that provide the templates for building the proteins cFos, Δ∆FosB, 

BDNF, and Cdk5, among others. Researchers 

have linked the resulting higher brain levels of 

some of these proteins with long-term consequences of chronic drug abuse. For example, 

accumulation of long-lasting Δ∆FosB correlates 

with cocaine craving and drug self-administration in animals, and may contribute to longlasting structural changes 

in cocaine abusers’ brain reward systems. As researchers 

continue to trace out the consequences of cocaine-induced 

gene activation, Dr. Nestler and colleagues pursued a 

related inquiry: How does it happen? Their candidate 

explanation was chromatin remodeling, a basic mechanism cells use to alter levels of the body’s vast array of 

proteins to suit new circumstances and challenges (see 

“Experience Restructures Chromatin”).

Chromatin consists of the deoxyribonucleic acid (DNA) 

double helix that carries an organism’s genes wrapped 

around complexes of histone proteins. The unit of chromatin is called the nucleosome, and chemical processes 

control how tightly packed nucleosomes are. Chromatin 

remodeling occurs when this packing becomes more or 

less compact. As the nucleosomes bunch up or spread out, 

some genes move into positions that increase—and others 

into positions that decrease—their ability to interact with 

RNA polymerase, the enzyme that executes the first step 

in protein building. This helps determine how much of 

the protein blueprinted by each gene will be made.

To test their hypothesis that cocaine activates genes by 

inducing chromatin remodeling, Dr. Nestler and his team 

compared tissue taken from the striatum of rats exposed 

to the drug and others given saline. Specifically, they 

assayed the tissue for the end products of two chemical 

reactions known to modify chromatin’s shape: acetylation 

and phosphoacetylation of its primary molecular components, histone 3 (H3) and histone 4 (H4). Both of these 

reactions remodel chromatin in ways that increase gene 

expression.

The findings bore out the hypothesis. Within 30 minutes 

of a single injection, the chromatin associated with the 

cFos gene in the cocaine-exposed animals contained twice 

as much acetylated H4 than that in the control animals, 

and phosphoacetylated H3 also was higher. The time 

course of these effects jibed with previous observations 

that cocaine induces a rapid, transient increase in levels of 

the cFos protein. They were no longer present in tissues 

taken 3 hours after the injection, and they stopped occur25
ring when animals were given repeated cocaine doses over 

an extended period. These data support scientists’ conception of the cFos gene as an early responder to acute neural 

disruptions, with little or no direct role in situations of 

recurrent disruption.

As with cFos, a single cocaine injection elevated acetylated 

H4 in chromatin linked to the FosB gene, but the levels 

returned to baseline within 3 hours. Repeated cocaine did 

not induce H4 acetylation in FosB geneassociated chromatin, but did cause H3 acetylation. The researchers say 

that the switch from H4 acetylation after a single cocaine 

exposure to H3 acetylation after chronic exposure may 

mark a turning point in developing addiction.

“More research is needed to identify the specific molecular 

basis of this switch,” says Dr. Nestler. “However, prior 

work in my laboratory and with collaborators is starting 

to fill in a picture of why H3 acetylation and FosB’s activation and subsequent triggering of Δ∆FosB after chronic 

cocaine might be important. We believe that this series 

of molecular events, and probably others, mediate the 

long-term behavioral and neural changes that underlie the 

transition from drug abuse to addiction,” says Dr. Nestler. 

The experiments and assays also showed:

• A single cocaine injection did not affect BDNF or 

Cdk5 gene-associated chromatin, but chronic exposure 

induced H3 acetylation of both. Once initiated, the 

effects were long-lasting. The 

quantities of modified H3 in 

BDNF gene-associated chromatin 

in exposed animals increased from 

3-fold of those of salinetreated 

animals at day 1 to 14-fold at day 

7. Acetylated H3 related to the 

Cdk5 gene were more than twofold those of saline 1 day after 

the last injection, and started to 

return to control levels only 7 

days after cocaine cessation. Such 

persistent and robust gene activation long after the last dose of 

cocaine is striking in contrast with 

the relatively short-lived activation 

observed for cFos and FosB.

• Elevations in the ∆FosB protein 

selectively activated Cdk5—the 

only gene examined in the study 

that was turned on in this way. 

This finding suggests that ∆FosB 

may influence histone modifications by recruiting the chemical 

agents of chromatin remodeling 

to some target genes.

“Understanding how cocaine turns on these genes could 

help addiction researchers develop potential treatments 

that counteract the effects of drug abuse at the molecular 

level. Agents that reverse chromatin remodeling are available, and we are examining whether they block cocaine’s 

cellular effects,” says Dr. Nestler.

“Taken together with other studies showing that drugs 

induce long-term structural changes to brain cells, Dr. 

Nestler’s findings show that chromatin remodeling is one 

way that such neural modification might occur. Such 

alterations are not necessarily permanent, and studies are 

needed to determine whether abstinence or other behavioral modifications further restructure chromatin to a 

state similar to that seen prior to drug exposure,” says Dr. 

Joni Rutter of NIDA’s Division of Basic Neuroscience 

and Behavioral Research. Whether nonstimulant drugs of 

abuse also act through chromatin remodeling is another 

important area for future research, she says.

A Connection With Cocaine-Related Behavior

In other experiments, Dr. Nestler and colleagues linked 

chromatin remodeling to cocaine’s behavioral effects by 

examining its role in a laboratory stand-in for human 

cueinduced drug seeking called conditioned place preference (CPP). By exhibiting CPP—lingering in a part 

of a cage where it has received a drug—an animal indicates that it is seeking more of the drug (see “Animal 

26
Experiments in Addiction Science” NIDA Notes, Vol. 20, 

No. 5). The researchers hypothesized that augmenting or 

preventing histone modifications during drug administration sessions would increase or decrease CPP, respectively.

The investigators administered 

cocaine to mice daily for 4 days. 

Before each administration, they 

treated one group with a drug 

that enhances histone acetylation 

(trichostatin A, TSA) and another 

with a virus that expresses an 

enzyme that blocks this particular 

modification (herpes simplex virus, 

HSV). When placed back in the 

test cage on day 5, the group given 

TSA doubled the time spent in the 

drug-associated cage, on average, 

relative to the control group. In 

contrast, the group given the HSV 

vector lingered in the test cage for 

one-third of the time spent by its 

control group.

The findings suggest a causal 

link between histone acetylation 

in the striatum and sensitivity to 

cocaine’s behavioral effects.

“The team had already demonstrated that chromatin remodeling plays a role in the rewarding aspects of cocaine abuse by 

including a group of animals that 

selfadministered the drug in the 

study. Their CPP experiment further strengthens the connection 

between histone restructuring and 

behavioral aspects of addiction and 

suggests that agents that reverse 

chromatin restructuring hold 

promise as potential therapies,” 

says Dr. Rutter.

Source

• Kumar, A., et al. Chromatin 

remodeling is a key mechanism underlying cocaineinduced plasticity in striatum. Neuron 48(2):303-314, 

2005. 

27
28

Impacts of Drugs on Neurotransmission

The defining features of drug intoxication and addiction can be traced to disruptions in cell-to-cell signaling.

By Carl Sherman, NIDA Notes Contributing Writer 

Research Findings

Volume 21, Number 4 (October 2007)

Drugs of abuse alter the way 

people think, feel, and behave 

by disrupting neurotransmission, the process of communication between brain cells. 

Over the past few decades, 

studies have established that 

drug dependence and addiction are features of an organic 

brain disease caused by drugs’ 

cumulative impacts on neurotransmission. Scientists continue to build on this essential 

understanding with experiments to further elucidate the 

physiological bases for drug abuse vulnerability as well as 

the full dimensions and progression of the disease. The 

findings provide powerful leads to new medications and 

behavioral treatments.

This second article in our NIDA Notes Reference Series

discusses the central importance of studying drugs’ effects 

on neurotransmission and describes some of the most 

common experimental methods used in this research. As 

with other articles in the series, we provide illustrative 

references from articles published in NIDA Notes.

What Is Transmission?

A person reads. The words on the page enter the brain 

through the eyes and are transformed into information 

that is relayed, from cell to cell, to regions that process 

visual input and attach meaning and memory. When 

inside cells, the information takes the form of an electrical 

signal. To cross the tiny intercellular gap that separates 

one cell from the next, the information takes the form of 

a chemical signal. The specialized chemicals that carry the 

signals across the intercellular gaps, or synapses, are called 

neurotransmitters.

The ebb and flow of neurotransmitters—neurotransmission—is thus an essential feature of the brain’s response to 

experience and the environment. To grasp the basic idea 

of neurotransmission, compare the brain to a computer. 

A computer consists of basic units (semiconductors) that 

are organized into circuits; it processes information by 

relaying electric current from unit to unit; the amount 

of current and its route through the circuitry determine 

the final output. The brain’s corresponding basic units 

are the neurons—100 billion of them; the brain relays 

information from neuron to neuron using electricity and 

neurotransmitters; the volume of these signals and their 

routes through the organ determine what we perceive, 

think, feel, and do.

Of course, the brain, a living organ, is much more complex and capable than any machine. Brain cells respond 

with greater versatility to more types of input than any 

semiconductor; they also can change, grow, and reconfigure their own circuits.

The Basic Research Questions

Neuroscientists seeking to understand why a drug is abused 

and the consequences of that abuse focus on two issues:

• Which neurotransmitter or neurotransmitters does 

it affect?

• How does it alter neurotransmission?

Which Neurotransmitter or Neurotransmitters Does 

the Drug Affect?

A person’s experiences when abusing a drug reflect the 

functional roles of the particular neurotransmitter whose 

activity it disrupts. Each individual neuron manufactures 

one or more neurotransmitters: dopamine, serotonin, 

acetylcholine, or any one of a dozen others that scientists 

have discovered to date. Each neurotransmitter is associated with particular effects depending on its distribution 

among the brain’s various functional areas. Dopamine, 

for example, is highly concentrated in regions that regulate motivation and feelings of reward, accounting for its 

importance in compulsive behaviors such as drug abuse. 

A neurotransmitter’s impact also depends on whether it 

stimulates or dampens activity in its target neurons.

Some drugs primarily disrupt one neurotransmitter or 

class of neurotransmitters. For example, opioid drug 

abusers experience changes that are similar to—but more 

pronounced than—those that accompany normal fluctuations in the brain’s natural opioid-like neurotransmitters, 

endorphin and enkephalin: increased analgesia, decreased 

alertness, and slowed respiration (see table). Other drugs 

interact with more than one type of neurotransmitter. 

Cocaine, for example, attaches to structures that regulate 

dopamine, thereby producing euphoria; however, cocaine 
29

also produces changes in norepinephrine and glutamate, 

which are the sources of its stimulant effects.

Because a neurotransmitter often stimulates or inhibits 

a cell that produces a different neurotransmitter, a drug 

that alters one can have secondary impacts on another. In 

fact, the key effect that all abused drugs appear to have in 

common—a dramatic increase in dopamine signaling in 

the nucleus accumbens (NAc), leading to euphoria and 

a desire to repeat the experience—is in many cases an 

indirect one. For example, nicotine stimulates dopaminereleasing cells directly by stimulating their acetylcholine 

receptors, and also indirectly by triggering higher levels of 

glutamate, a neurotransmitter that acts as an accelerator 

for neuron activity throughout the brain.1

How Does the Drug Alter Neurotransmission?

Neurotransmission is a cyclic process that transpires in 

several steps utilizing specialized components of the sending and receiving cells (see “Getting the Message Across”). 

Identifying the precise step that a drug disrupts, and how, 

provides crucial insight into its impact on abusers and is 

key to identifying medical and behavioral interventions to 

inhibit, counter, or reverse the disruption.

Some drugs mimic neurotransmitters. Opioid drugs such as heroin and 

OxyContin, for example, chemically 

resemble the brain’s natural opioids sufficiently to engage and stimulate their 

specialized receptors. Since heroin stimulates many more receptors than the brain 

uses in the normal cycle of endorphin 

and enkephalin release and uptake, the 

result is a massive amplification of opioid 

activity. Marijuana and hashish mimic 

cannabinoid neurotransmitters, the most 

important of which is anandamide. 

Nicotine attaches to receptors for acetylcholine, the neurotransmitter for the 

cholinergic system.

Some drugs alter neurotransmission by 

interacting with molecular components 

of the sending and receiving process other 

than receptors. Cocaine, for example, 

attaches to the dopamine transporter, 

the molecular conduit that draws freefloating dopamine out of the synapse 

and back into the sending cell. As long 

as cocaine occupies the transporter, dopamine cannot reenter the cell by this 

route. It builds up in the synapse, stimulating receiving cell receptors more copiously and producing much greater dopamine impact on the receiving cells than 

occurs naturally. “Cocaine’s Dopamine 

Connections” enumerates some of cocaine’s interactions 

with the mechanisms of dopamine signaling, and how 

they motivate abuse and contribute to dependence and 

addiction.

Finally, some drugs alter neurotransmission by means 

other than increasing or decreasing the quantity of receptors stimulated. Benzodiazepines, such as diazepam or 

lorazepam, enhance receiving cells’ responses when the 

neurotransmitter gamma-aminobutyric acid (GABA) 

attaches to their receptors. Benzodiazepines’ relaxation 

effects result from this increased sensitivity to GABA’s 

inhibitory impact on cellular activity.

What Changes Occur With Chronic Drug Abuse?

During the early phase of an individual’s drug experimentation, neurotransmission normalizes as intoxication wears 

off and the substance leaves the brain. Eventually, however, drugs wreak changes in cellular structure and function 

that lead to long-lasting or permanent neurotransmission 

abnormalities. These alterations underlie drug tolerance, 

addiction, withdrawal, and other persistent consequences.
30

Some longer term changes begin as adjustments to compensate for drug-induced increases in neurotransmitter 

signaling intensities. For example, drug tolerance typically develops because sending cells reduce the amount 

of neurotransmitter they produce and release, or receiving cells withdraw receptors or otherwise dampen their 

responsiveness. Scientists have shown, for example, that 

cells withdraw opioid receptors into their interiors (where 

they cannot be stimulated) when exposed to some opioid 

drugs; when exposed to morphine, however, cells appear 

instead to make internal adjustments that produce the 

same effect—reduced responsiveness to opiate drugs and 

natural opioids.2

 Over time, this and related changes 

recalibrate the brain’s responsiveness to opioid stimulation downward to a level where the organ needs the extra 

stimulation of the drug to function normally; without the 

drug, withdrawal occurs.

The drug-related mechanisms producing cumulative 

changes in neurotransmission sometimes are genetic in 

nature. While a drug cannot change a person’s genes, 

drugs can prod some genes to increase their production of 

proteins, leading to changes in cell function or even actual 

reshaping of the physical structure of cells. For example, 

in rats, cocaine and amphetamine stimulate genes that 

produce the proteins used to build dendrites, branch-like 

cell structures that contain neurotransmitter receptors.3

Brains normally sprout new dendrites as they register new 

learning; the accelerated dendrite formation stimulants 

induce may partially account for these drugs’ unusual hold 

on an abuser’s attention.

Some drugs are toxic to nerve cells, and the effect accumulates with repeated exposures. For example, the club 

drug methylenedioxymethamphetamine (MDMA, ecstasy) 

damages axons that release serotonin; the result is disruption of serotonin neurotransmission that likely underlies 

the long-lasting memory problems experienced by abusers.4

 Similarly, methamphetamine, over time, damages 

enough dopamine-sending cells to cause significant defects 

in thinking and motor skills; with abstinence, dopamine 

function can partially recover, but it is unclear whether 

cognitive and motor capabilities come back as well.5

Experimental Methods

To determine whether or how a drug affects a particular 

neurotransmitter, researchers typically will compare individuals who have a history of drug exposure with others 

who do not. If researchers are investigating links between 

a drug’s impact on neurotransmission and a drug-related 

behavior or symptom, they may compare individuals who 

exhibit the behavior or symptom with others who do 

not. The subjects in these experiments may be animals or 

people. In the case of animals, drug exposure often takes 

place under laboratory conditions designed to mimic 
31

human drug consumption. Studies 

can be divided into those in which 

measurements are made in living 

animals or people and those in which 

animal brain tissue is removed and 

examined.

Brain Tissue Assays

With removed tissue, scientists may 

perform chemical assays to quantify 

the presence of a neurotransmitter, 

receptor, or other structure of interest. In a recent experiment, scientists 

assayed brain tissue from 35-day-old 

rat pups and found that those that had 

been exposed to nicotine in utero had 

fewer nicotine receptors in the reward 

system than unexposed rats.

6

A second experimental method using 

removed brain tissue—in vitro, liter 

ally, in glass, a historical term referring 

to the containers for the tissue and 

solution—enables researchers to view 

a drug’s effects on neurotransmission 

in action. Scientists place the tissue in 

a laboratory solution of nutrients that 

enables the cells to continue to carry 

out some of their living functions. The 

researchers may then, for example, 

add the drug being investigated to the 

solution and monitor whether the cells 

respond by increasing their release of 

neurotransmitters. Alternatively, they 

may measure cell membrane or electrical properties that stimulate or inhibit 

the release of neurotransmitters.

In both in vitro experiments and in 

living animals, the techniques for 

measuring neurotransmitter quantities 

and fluctuations include microdialysis and fast-scan cyclic voltammetry 

(FSCV). Microdialysis involves taking 

a series of samples of the intercellular 

fluid containing the neurotransmitter 

through a microscopic tube inserted 

into the tissue or living brain. FSCV, 

recently developed by NIDA-funded 

scientists, monitors neurotransmitter fluctuations at tenth-of-a-second 

intervals by measuring electrical 

changes related to neurotransmitter 

concentrations.

7
32

Live Studies

Studies with living animals or people are essential for tying 

drugs’ effects on neurotransmitters to behaviors or symptoms. A common design for experiments with either animals or people is to give study subjects a chemical that has 

a known effect on a particular neurotransmitter, and then 

observe the impact on their behavior. Typically, the chemical is either an agonist (promoter) or antagonist (blocker) 

of signaling by the neurotransmitter.

In a recent experiment, for example, a research team 

administered a glutamate agonist to rats and showed that 

the resulting increased levels of the neurotransmitter correlated with a reduction in the animals’ cocaine seeking.8

Another team using the same strategy implicated glutamate in nicotine withdrawal.9

 Such studies are a staple 

of testing compounds to identify medication classes with 

potential for treating abuse or addiction.

Researchers also genetically alter animals to have special 

characteristics, such as producing less or more than the 

normal amounts of a particular neurotransmitter, or lacking receptors for a neurotransmitter. Researchers expose 

such animals to a drug and observe whether the animals’ 

display of some particular drug-related behavior—for 

example, pacing restlessly after being given a stimulant—

increases or decreases.

Brain Scans

Brain imaging techniques enable neuroscientists to directly 

assess neurotransmission in people and living animals. 

With positron emission tomography (PET), researchers can compare groups of drug-abusing and nonabusing 

individuals, quantifying differences in their levels of a particular neurotransmitter molecule (e.g., dopamine) or neurotransmission component (e.g., a receptor or transporter). 

With PET, researchers also can correlate a drug’s transit 

through the brain with fluctuations in a target neurotransmitter. They can elicit a drug-related behavior or symptom (e.g., craving) and relate neurotransmitter fluctuations 

to the rise and fall in its intensity.

One recent PET study, for example, showed that smokers 

have less of the neurotransmitter-degrading enzyme monoamine oxidase-B (MAO-B) throughout their bodies than 

nonsmokers.10 The relative deficit of MAO-B may help 

explain why smokers are at higher risk for hypertension 

and other chronic diseases.

Researchers use both PET and functional magnetic resonance imaging (fMRI) to monitor metabolic activity in 

selected regions of the brain. Because each neurotransmitter has a unique distribution among the regions of the 

brain, information on locations of heightened or decreased 

activity provides clues to which neurotransmitter is affected under the conditions of the study.

Summary

By altering neurotransmission, addictive drugs produce 

effects that make people want to continue to abuse them 

and induce health problems that can be longlasting and 

profound. The effects are drug-specific: Each drug disrupts 

particular neurotransmitters in particular ways. Some 

important effects, however, are shared by all: initial pleasurable feelings, and subsequent dependence and addiction, resulting from disruption of the dopamine 

neurotransmitter system.

Scientists use a wide variety of experimental tools and 

techniques to study drugs’ effects on neurotransmission, 

and their consequences, in both animals and people. Their 

findings enhance our understanding of the experiences of 

drug abusers and the plight of addicts, point the way to 

new behavioral and medication treatments, and provide 

potential bases for prevention strategies and monitoring 

progress in treatment.

Sources

1

“Nicotine’s Multiple Effects on the Brain’s Reward 

System Drive Addiction,” NIDA Notes 17-6. 

2

“Genetic Engineering Studies May Lead to 

Development of More Effective Pain Relievers,” 

NIDA Notes 15-3. 

3

“Stimulant Drugs Limit Rats’ Brain Response to 

Experience,” NIDA Notes 19-3. 

4

“Ecstasy Damages the Brain and Impairs Memory 

in Humans,” NIDA Notes 14-4. 

5

“Methamphetamine Abuse Linked to Impaired 

Cognitive and Motor Skills Despite Recovery of 

Dopamine Transporters,” NIDA Notes 17-1. 

6

“Nicotine Alters the Developing Rat Brain,” 

NIDA Notes 21-2.

7

“Microscopic Probe Detects Changes in Brain 

Chemistry as They Occur,” NIDA Notes 19-1. 

8

“Brain Glutamate Concentrations Affect Cocaine 

Seeking,” NIDA Notes 19-3.

9

“Nicotine Withdrawal Linked to Disrupted Glutamate 

Signaling,” NIDA Notes 19-6. 

10“Smoking Decreases Key Enzyme Throughout Body,” 

NIDA Notes 19-1. 
Serotonin System May Have Potential as a Target for Cocaine 

Medications 

By targeting specific receptors of the neurochemical serotonin, investigators hope to advance the 

development of potential relapse prevention agents.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 3 (April 2007)

NIDA-supported researchers have weakened rats’ behavioral responses to environmental cocaine cues by manipulating the neurotransmitter serotonin. Moreover, such 

manipulation can make the drug seem less stimulant-like 

to the rats. The findings suggest that medications that act 

on the serotonin system might help recovering cocaine 

abusers sustain abstinence, say Dr. Kathryn Cunningham 

and colleagues at the Center for Addiction Research at the 

University of Texas Medical Branch in Galveston and the 

Polish Academy of Sciences in Krakow.

While cocaine makes its primary pharmacological 

impact on the neurotransmitter dopamine, it also increases levels of other chemical messengers, including serotonin 

(5-HT). Previous research with animals has shown that 

5-HT2C and 5-HT2A receptors—two proteins on brain 

cell surfaces that mediate serotonin’s effects on cellular 

activity—regulate behavioral responsiveness to cocaine. 

For example, activating the 5-HT2C receptor reduces the 

animals’ typical behavioral responses to cocaine—including hyperactivity, self-administration, and return to drugseeking following abstinence. Dr. Cunningham’s studies 

showed that the 5-HT2C receptor affected responsiveness 

to cocaine-associated environments, and 

that both receptors affected the animals’ 

experience of the drug.

Hyperactivity and Discrimination

Dr. Cunningham and colleagues first 

examined the effect of manipulating 

5-HT2C receptors on a behavior called 

conditioned hyperactivity: When 

researchers repeatedly move an animal 

from its home cage and give cocaine in 

a test cage, the drug-paired environment 

comes to evoke the same behavioral 

effect as the stimulant itself when saline 

is administered, so that the animal starts 

moving about restlessly as soon as it finds 

itself in the cage. Experience has shown 

that compounds that inhibit conditioned 

hyperactivity usually also reduce behaviors that are laboratory stand-ins for 

human relapse.

Dr. Cunningham and colleagues administered cocaine (15 

mg/kg) to rats daily for 7 days in a test cage. Two days 

later, they gave some of the rats a compound that activates 

the 5-HT2C receptor (MK 212), some a compound that 

blocks it (SB 242084), and others saline, and returned the 

animals to the test cage. Compared with the saline-treated 

animals, who showed the usual conditioned hyperactivity, rats given the 5-HT2C-receptor-stimulating compound 

moved around less (by about 40 percent), while those that 

received the blocker showed an exaggerated hyperactive 

response (by 25 percent) to the test cage. A separate group 

of animals was given cocaine only in their home cage 

and saline in the test cage. These animals showed normal 

activity when tested 2 days later, which was unaffected by 

the 5-HT2C receptor compounds. These data strengthen 

the conclusion that the 5-HT2C receptor is important in 

the cocaine-environment link.

In another study, Dr. Cunningham’s team used an experimental protocol called drug discrimination to determine 

whether compounds that act at the 5-HT2C and 5-HT2A

receptors would alter the way cocaine made the rats feel 

(see textbox, below). Prior research had indicated that the 

33
two receptors oppose each others’ effects on the cocaine 

response, and the researchers hypothesized that blocking 

the 5-HT2A receptors would make cocaine feel less stimulant-like to the rats, whereas inhibiting 5-HT2C receptors 

would enhance the drug’s effects. Rats given a compound 

that blocks 5-HT2A receptors (SR 46349B) prior to 

cocaine reduced their pressing on the lever associated with 

cocaine’s effects compared with one linked with saline. 

Animals pretreated with a compound that blocks 5-HT2C 

receptors (SDZ SER-082) increased their pressing on the 

cocaine lever over the saline lever. The results bore out the 

hypothesis.

“Taken together, the findings of these studies 

support the idea that the serotonin 

5-HT2C receptor plays a role in linking 

environmental cues and the experience 

of cocaine, as well as the subjective 

effects of the drug. The 5-HT2A

receptor also influences these behaviors, 

but in the opposite direction,” says Dr. 

Cunningham. “From the medication 

development perspective, a drug with 

dual action at both receptors—that is, 

one that simultaneously stimulates the 

5-HT2C receptor and blocks the 5-HT2A

receptor—might be effective in reducing cue-induced craving. We know of 

no such compound, and our team is 

working to develop one.” She adds that 

agents that stimulate 5-HT2C or inhibit 

5-HT2A receptors do not fully mimic 

cocaine or affect other behaviors, suggesting limited side effects.

“It is not really surprising that serotonin is implicated in addiction given 

its importance to essential behaviors—

including sleep, eating, mood, cognitive 

processes, and self-regulation—and its 

influence on dopamine,” says Dr. Minda 

Lynch of NIDA’s Division of Basic 

Neuroscience and Behavioral Research. 

“Serotonin influences dopamine in the 

brain’s reward pathway and cortex, so 

examining the behavioral effects of serotonin-influencing compounds in animals 

is a reasonable approach in the investigation of potential pharmacotherapies,” 

says Dr. Lynch. She agrees that a dualaction compound that operates on the 

serotonin 5-HT2C and 5-HT2A receptors 

might eventually help prevent relapse. 

“However, a great deal of further testing 

in animals is needed. A good next step 

would be to confirm the findings in 

animal protocols that mimic cue-induced relapse,” says 

Dr. Lynch.

Sources

• Liu, S., and Cunningham, K.A. Serotonin (2C) 

receptors (5-HT(2C)R) control expression of cocaineinduced conditioned hyperactivity. Drug and Alcohol 

Dependence 81(3):275-282, 2006.

• Filip, M.; Bubar, M.J.; and Cunningham, K.A. 

Contribution of serotonin (5-HT) 5-HT2 receptorsubtypes to the discriminative stimulus effects of 

cocaine in rats. Psychopharmacology 183(4):482-489, 

2006. 

34
Brain Changes Accompany Cocaine Withdrawal 

Research Findings

Volume 21, Number 2 (February 2007)

Rats repeatedly exposed to cocaine and then withdrawn from it exhibit neural 

changes in the lateral amygdala, a part of the brain involved in responding to pleasurable and aversive stimuli. Such changes may mediate the negative emotional 

effects that accompany drug withdrawal, say the researchers who documented the 

effect in a recent study. Dr. Vadim Bolshakov and colleagues at Harvard Medical 

School have shown that long-term potentiation (LTP), a process underlying learning and memory, occurs in the lateral amygdala when cocaine-exposed rats no longer have access to the drug. They found a clear link between LTP and enhanced 

levels of the neurotransmitter glutamate in the lateral amygdala and signs of 

withdrawal in the rats. The findings suggest that amygdala circuits might contribute to drug modulation of motivational 

states and influence addictive behaviors.

Source

• European Journal of Neuroscience 23(1):239-250, 2006. 

35
Cocaine Craving Activates Brain Reward Structures; Cocaine 

“High” Dampens Them

A study documented changing emotional and neurobiological responses to cocaine with successive doses 

during a single session of drug taking.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 2 (February 2007)

NIDA-funded researchers mapped the dynamic of druginduced brain activity and emotional responses that occur 

during a cocaine abuser’s typical binge-like pattern of 

self-administration. Dr. Robert Risinger and colleagues at 

the Medical College of Wisconsin found that craving corresponds with increased activity in key brain areas underlying reward and motivation, while the cocaine-induced 

“high” is linked with decreased activity in these same 

regions. “Our results suggest that, as one takes multiple 

‘hits’ of cocaine, pleasure accumulates with each successive 

dose, but lasts for a shorter time—a pattern that would 

compel people to keep abusing,” he says.

“My colleagues and I wanted to know what cocaine 

does to the brain to compel drug-seeking behavior in 

addicted people—particularly, why taking a small amount 

of the drug can lead to a binge. Understanding this could 

help identify interventions to stop such abuse,” says 

Dr. Risinger. 

Dr. Risinger’s team recruited six cocaine-addicted men 

who were not seeking treatment. The men, aged 23 to 41, 

had abused crack cocaine for 11 years, on average. They 

completed a medical examination, received counseling 

on the health consequences of cocaine abuse, and were 

offered (but all declined) addiction treatment before 

the study.

Each man participated in two 1-hour sessions of cocaine 

self-administration. At the beginning of the first session, 

he learned how to press a joystick button to receive infusions of cocaine through an intravenous catheter. After a 

5-minute baseline period, he saw a computer-displayed 

signal that the joystick was activated, and for the next 55 

minutes he pressed the button at will. Each press delivered 

a 20 mg/70 kg of body weight dose of the drug—except 

that, for safety reasons, doses could not be repeated at 

intervals of less than 5 minutes, and total doses over the 

course of the hour were limited to six. Meanwhile, in 

response to prompts on a computer display, the volunteer 

used a joystick to rate his cocaine craving, high feelings, 

and other sensations once per minute. During the second 

session, the researchers used functional magnetic resonance imaging (fMRI) to obtain brain scans synchronized 

with the subjective reports. After each session, each man 

underwent a brief physical examination and left the facil36

Red areas 

in circles Blue areas 

in rectangles
ity once his vital signs returned to baseline levels and he 

no longer showed drug effects or reported craving.

Behavioral Results

Participants administered 4.5 injections a session, on average, spacing the doses about 7.4 minutes apart. Only two 

administered the maximum six doses. “For many patients, 

the amount of cocaine consumed during a self-administration session was less than they typically abused,” says 

Dr. Risinger.

As anticipated, the men’s feelings of being high decreased 

before and increased after cocaine administration. From 

the first through the fourth injection, 

the intensity of each successive high was 

greater, and its duration shorter. Craving 

peaked about 1 minute before each injection and decreased to a low point about 

2 minutes after cocaine administration, 

before rising again during minutes 3 to 4. 

Absolute levels of craving decreased with 

each successive injection, but the preadministration increase in craving rose more sharply. 

Dr. Risinger says the participants’ reports match other 

abusers’ accounts of their feelings during binges: “People 

often talk about ‘chasing the high.’ They abuse the drug 

several times in an episode, feel increasingly high with the 

first few hits, and experience a rapid dropoff in the duration of pleasure with repeated use—which may explain 

consuming larger amounts and more frequently over a session. Consuming cocaine satisfies craving only briefly, and 

then the feeling increases again before another administration, which may also contribute to the binge pattern.”

“It is not clear whether the subjective feeling of craving 

was directly responsible for driving the participants to 

self-administer, or whether some other process, perhaps 

response-outcome learning, was responsible for initiation of self-administration,” says Dr. Steven Grant of 

NIDA’s Division of Clinical Neuroscience and Behavioral 

Research. 

Imaging Findings

Cocaine-induced craving was associated with increased 

neural activity in brain areas involved in reward anticipation, emotional response, and control over actions: the 

nucleus accumbens (NAc), the orbitofrontal cortex, and 

the anterior cingulate cortex. The findings accord well 

with those of cue-induced craving studies, which generally 

indicate that the anticipation of a reward is accompanied 

by activation of the dopamine-rich mesolimbic pathway—

a neural circuit involved in reward, motivation, and 

directing attention to stimuli. Such a neural response is 

thought to “set up” the brain to experience reward and to 

drive goal-directed behavior. 

The researchers also found that cocaine-induced euphoria 

depressed activity in the areas activated by craving (see 

figure, page 4). In prior studies, Dr. Risinger’s team has 

observed NAc suppression in participants who reported 

experiencing a cocaine-induced high. Although researchers 

do not yet fully understand the neurobiological mechanisms underlying the high, some have speculated that suppression of NAc firing may be an important component, 

perhaps reflecting altered receptor sensitivity or weakened 

stimulation from other brain structures. Another research 

team found that participants who reported feeling high 

after receiving a single researcher-controlled dose of 

cocaine exhibited increased activity in the NAc. The 

different findings may reflect the teams’ divergent 

experimental methods.

The study represents an important step in correlating 

drug-induced craving and high with neural activity in 

specific regions of the human brain. “It provides insight 

into the neurobiology involved in drug-taking binges, a 

very common and dangerous behavior associated with the 

disease of addiction,” says Dr. Risinger. 

“Dr. Risinger’s study is a good example of translational 

research, which applies a well-established technique in 

 animal research to people. Although the results need replication in a larger number of participants, the findings are 

provocative because they raise good questions about the 

relationship between the various neurobiological responses—the fMRI signal and dopamine release, for example. 

We currently do not have a complete picture 

of how neurochemical responses and neural activation 

patterns exactly relate to the entire drug-taking experience, 

but this issue can be addressed in reverse translational 

research—animal imaging studies of self-administration 

and passive cocaine delivery,” says Dr. Grant. NIDAfunded investigators are developing such techniques, 

he adds.

Source 

• Risinger, R.C., et al. Neural correlates of high and 

craving during cocaine self-administration using 

BOLD fMRI. NeuroImage 26(4):1097-1108, 2005. 

37

The study represents an important step in correlating drug-induced craving and high with neural 

activity in specific regions of the human brain.
Cocaine Abusers’ Pretreatment Cue Responses Predict Recovery 

Success

In the future, patients’ brain scans may help clinicians tailor addiction treatment to improve therapeutic 

outcomes.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 2 (February 2007)

A recent NIDA study strengthens prospects that brain 

imaging may one day help clinicians assign individual 

patients to treatment models that maximize their personal chances of a successful outcome. The study, conducted by Dr. Thomas Kosten and colleagues at Yale 

University School of Medicine, the University of Arkansas 

for Medical Sciences, and the Massachusetts Institute of 

Technology, correlated cocaine-addicted patients’ regional 

brain responses to drug cues with their outcomes in 

subsequent treatment. The patients whose brain scans 

revealed rapid and strong activation in sensory, motor, 

and cognition- and emotion-processing brain areas were 

more likely to drop out of treatment and fail to achieve 

stable abstinence.

“A test that predicts treatment outcomes, especially vulnerability to relapse, could help guide individualized 

treatment. For example, a clinician might recommend 

an extended stay in residential treatment or more intense 

behavioral intervention for patients with a propensity 

for relapse,” says Dr. Kosten, now at Baylor College 

of Medicine.

Dr. Kosten and colleagues pursued the implications of an 

intriguing finding made in a prior study of cocaine cue 

responses: In some patients, strong, rapid activation of 

brain areas associated with emotion and sensing preceded 

the onset of craving. Although craving itself does not 

generally predict relapse, Dr. Kosten’s team speculated 

that cue-induced brain activation that occurs quickly and 

reflexively, below awareness, might do so. They hypothesized that patients who showed such responses during the 

first 30 seconds of cue exposure would also demonstrate 

poorer treatment outcomes.

To test their hypothesis, the investigators recruited 17 

men and women who were participating in a trial of an 

antidepressant—sertraline—that is being evaluated as a 

possible treatment for cocaine addiction. The participants 

reported abusing cocaine 20 days, on average, during the 

month before the study. All met standard clinical criteria 

for cocaine addiction and had abused the drug for 6 years, 

on average. Most were new to treatment.

After being cocaine-free for 5 days, on average, each participant underwent functional magnetic resonance imaging (fMRI) while watching two 4-minute videotapes. The 

first minute of each tape reported on vegetable prices, and 

the participants’ brain activity while hearing this emotionally neutral information served as a baseline for comparison. During the last 3 minutes, an actor pretended to 

smoke cocaine and experience a “rush.” Immediately after 

viewing the tapes, each participant rated peak cocaine 

craving intensity on a scale from 0 to 10. After the imaging session, participants began taking either sertraline or a 

placebo daily and completed 2 weeks of residential treatment. During the 10-week outpatient phase of the trial, 

they were to continue their medication regimen, receive 

weekly individual cognitive-behavioral therapy, and submit urine samples three times a week.

38
Interplay Within Cingulate Cortex?

Nine of the 17 participants relapsed, defined by the 

investigators as submitting fewer than 15 of a possible 30 

cocaine-free samples during the study and not completing outpatient treatment. Participants taking sertraline 

were just as likely as those taking the placebo to relapse. 

Relapsers and nonrelapsers reported cue-induced cravings of comparable intensity. The two groups differed, 

however, on brain activation during the first 30 seconds 

of the cocaine-cue videotapes. Relapsers showed greater 

cue-induced activation than nonrelapsers in several areas 

of the cortex: the left precentral (movement control), right 

superior temporal (auditory processing), right lingual and 

right inferior occipital (visual processing), and the left posterior cingulate cortices. The cingulate cortex is integral to 

attention, response inhibition, emotional regulation, and 

decisionmaking (see chart). 

The relapsers’ greater activation of the posterior cingulate 

cortex (PCC) was the most notable of the findings. Also 

significant was the lack of any difference between the 

outcome groups in activation of the neighboring anterior 

cingulate cortex (ACC). This contrasts with findings from 

previous studies, in which ACC activation and craving 

were associated in patients who had longer abstinence 

(average 14-28 days) and were imaged for periods longer 

than 30 seconds after being shown cues. 

Taken together Dr. Kosten says, these results suggest that 

an interplay occurs between the PCC and ACC following 

exposure to cocaine cues and changes with increasing stability of abstinence. In patients highly vulnerable to cues, 

intense PCC activation occurs within 30 seconds of cue 

exposure and is positively associated with risk for relapse. In 

less vulnerable patients, early PCC activation is less intense, 

and these patients are able to activate the ACC to counter 

the association with relapse risk. 

Dr. Kosten’s findings highlight the promise of imaging 

linked to behavioral assessments as a tool for guiding the 

treatment of addictions and other psychiatric disorders. 

They parallel a previous NIDA-funded study in which 

brain activity patterns during a decisionmaking task predicted treatment outcomes among patients addicted to 

methamphetamine (see “Brain Activity Patterns Signal Risk 

of Relapse to Methamphetamine,” NIDA Notes , 

Vol. 20, No. 5).

“If researchers can determine changes in brain activity 

that predict responses to particular treatments, then clinicians could match therapy with individuals’ scan results or 

even monitor progress in therapy,” says Dr. Kosten. More 

generally, studies that examine biological and behavioral 

predictors of treatment response elucidate the physiology 

underlying addiction—particularly the neural circuitry 

integrating stress, craving, and the 

propensity to relapse. New tools—

for example, scanners that highlight 

brain areas that are working together—are expected to reveal more 

about these physiological processes. 

“With such functional connectivity 

imaging, one could examine how 

the anterior and posterior cingulate 

‘talk’ to each other during a drug cue 

or other experience,” says Dr. Rajita 

Sinha, an investigator in the 

Kosten study.

“Eventually, researchers will integrate 

the findings of such studies into a 

complete picture that will specify 

therapeutic pathways or help in the 

development of targeted medications to reduce relapse probability,” 

adds Dr. Harold Gordon of NIDA’s 

Division of Clinical Neuroscience 

and Behavioral Research.

39

“If researchers can determine 

changes in brain activity that predict 

responses to particular treatments, 

then clinicians could match therapy 

with individuals’ scan results or even 

monitor progress in therapy.”
Source

• Kosten, T.R., et al. Cue-induced brain activity changes and relapse in cocaine-dependent patients. 

Neuropsychopharmacology 31(3):644-650, 2006.

40
Behavioral Response to Novelty Foreshadows Neurological 

Response to Cocaine

Young rats’ engagement with novel objects correlates with cocaine-induced dopamine release, shedding 

light on the mechanisms of drug abuse vulnerability.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 2 (February 2007)

NIDA-supported researchers Dr. Cheryl Kirstein and Ms. 

Kirstie Stansfield at the University of South Florida have 

found that higher scores on tests of impulsivity and some 

behavioral responses to novelty correlate with a heightened biological response to cocaine in adolescent, but not 

adult, rats. The findings accord well with scientists’ widely 

shared view that developmental differences in brain systems that use the neurotransmitter dopamine underlie age 

differences in susceptibility to drug abuse.

Dr. Kirstein and Ms. Stansfield conducted a series of 

behavioral assays to rate rats’ relative responsiveness to 

novelty, then compared these results with measures of 

dopamine release in the reward pathway after an injection 

of cocaine. First, they put adolescent rats (34 days old, 

which is roughly equivalent to adolescence in people) and 

fully mature rats (59 days old, equivalent to human young 

adulthood) through four behavioral protocols. The tests 

measured activity in a new environment (how much the 

rat moved around when put into a new cage); impulsivity 

(how quickly it approached a new object placed into its 

cage); exploratory drive in response to a new object (how 

many times it approached the object in a given period of 

time); and attraction to new objects (what percentage of a 

given time interval was spent close to the object).

The researchers then injected the animals with saline and 

then, 2 hours later, with cocaine 20 mg/kg. Every 10 minutes, starting immediately after the saline injection and 

continuing until 2 hours after administering the cocaine, 

they measured the concentrations of the neurotransmitter 

dopamine and its major metabolite in the rats’ nucleus 

accumbens (NAc). The measurements were made using 

the technique of in vivo microdialysis. By the time of the 

last measurement, the drug had cleared the animal’s system.

On Most Tests, Age Matters

In their analysis, the researchers compared cocaineinduced dopamine release in animals that had responded 

above the mean level on each test (high responders, HR) 

to those who had scored below the mean (low responders, LR). The results revealed that among both the adult 

and adolescent rats, those that exhibited greater activity in a new environment also demonstrated enhanced 

dopamine release following a cocaine injection. This was 

the only test, however, in which age did not influence 

cocaine-induced dopamine 

release. The other behavioral assays revealed interactions between age and 

the response to novelty on 

cocaine-induced dopamine 

release in the NAc:

• Impulsivity—Adolescent 

rats with above-themean impulsivity scores 

released more dopamine in 

response to cocaine than 

their age mates who were 

LR. Mature rats exhibited no clear relationship 

between impulsivity and 

cocaine-induced dopamine 

response.

• Exploration of a new 

object—Adolescent rats 

41
with above-the-mean scores on 

this measure released more dopamine in response to cocaine 

than their age mates who were 

LR. Adult rats showed the opposite pattern: Animals with abovethe-mean scores showed attenuated cocaine-induced dopamine 

release compared with age mates 

who were LR. 

• Attraction to a new object—

Adolescent rats exhibited no clear 

relationship between reactivity 

on this assay and cocaine-induced dopamine release. 

Mature rats with above-the-mean scores released less 

dopamine in response to cocaine compared with their 

age mates who were LR. 

Dr. Kirstein’s finding that for all the animals, greater 

activity in a new environment corresponded with 

increased sensitivity to stimulants is consistent with earlier 

research. Her team’s mixed findings on the impulsivity 

and other novelty response tests indicates, she says, that 

those behaviors arise from different physiological mechanisms than does locomotor activity. “My colleagues and I 

think locomotor activity may reflect primarily dopamine 

activity in 

a brain circuit involved with generating and controlling 

movement. Novelty may instead differentially stimulate 

mesolimbic dopamine—a pathway implicated in attention 

as well as reward and motivation,” says Dr. Kirstein.

Inhibition Develops Later

The findings on the three tests where age affected the 

relationship between behavior and cocaine-induced dopamine release may reflect maturation of the brain’s reward 

circuit. When rats are adolescents, dopamine-producing 

and releasing cells in this circuit may be particularly sensitive both to novelty and to pharmacological stimulation. 

As part of normal neurological development, areas of 

the brain that dampen the activity of this circuit come 

“online” later, explaining the age-related differences 

observed in Dr. Kirstein’s study. “The mesolimbic pathway and the cortical areas that inhibit it to regulate dopamine release are not yet fully matured in the adolescent, 

and this may explain why the adolescent brain responds to 

drugs differently than the adult brain,” says Dr. Kirstein.

“The results of Dr. Kirstein’s study, along with other 

animal research on the interaction of drugs and developmental stage, indicate that the adolescent brain is more 

responsive to drugs than the adult brain—both neurochemically and behaviorally,” says Dr. Nancy Pilotte of 

NIDA’s Division of Basic Neuroscience and Behavioral 

Research. Studies that identify the physiological and 

behavioral processes underlying age-related susceptibility 

to addiction complement epidemiological work on the 

individual and social factors contributing to adolescent 

vulnerability to substance abuse.

Source

• Stansfield, K.H., and Kirstein, C.L. Neurochemical 

effects of cocaine in adolescence compared to adulthood. Developmental Brain Research 159(2):119-125, 

2005. 

42
43

Methylphenidate for Comorbid Cocaine Abuse, ADHD

Research Findings

Volume 21, Number 1 (October 2006)

In an inpatient study with 14 non-treatment-seeking volunteers, Columbia University researcher Dr. Stephanie 

Collins and colleagues reported that a regimen of 40-60 

mg/day of sustained-release methylphenidate (SR-MPH) 

reduced ratings on scales of “feel high,” “good drug 

effect,” and other measures of cocaine’s reinforcing effects 

among seven abusers affected by attention deficit hyperactivity disorder (ADHD). The medication increased the 

cardiovascular effects seen with cocaine alone, but not 

to dangerous levels. Although preliminary, the findings 

suggest that a therapeutic approach of using slow-acting 

stimulants to reduce craving for cocaine—parallel to the 

use of methadone or buprenorphine in opiate addiction—may be possible for cocaine-addicted patients with 

ADHD. Although the researchers did not formally assess 

SR-MPH’s effects on participants’ ADHD symptoms, 

they did not note any obvious benefits.

Source

• Drug and Alcohol Dependence 82(2):158-167, 2006. 
Research Findings

44

Brain Mechanism Turns Off Cocaine-Related Memory in Rats

An exploration of memory’s molecular basis suggests potential novel therapeutic approaches to 

cue-induced craving. 

By Patrick Zickler, NIDA Notes Contributing Writer

Volume 21, Number 1 (October 2006)

Scientists at the University of California, Irvine, have 

added to evidence that a brain enzyme controls key memory processes that link drug experiences, the surroundings 

in which they take place, and the urge to repeat them. In 

a series of experiments, inhibiting the enzyme attenuated 

a rat behavior that is a laboratory stand-in for human cueinduced drug-seeking. The findings suggest that in the 

future, therapeutically manipulating levels of the enzyme 

might cut addicted individuals’ vulnerability to environmental triggers for drug craving and abuse.

The NIDA-funded scientists, Drs. Courtney Miller and 

John Marshall, focused on the enzyme in an attempt to 

elucidate the ways cellular activities promote cue-induced 

drug-seeking. “Although studies have established that 

nerve cells in the core of the nucleus accumbens are 

critically involved,” Dr. Miller says, “we haven’t had much 

information about the molecular mechanisms that transform environmental cues into an urge to repeat drugassociated behavior.” One likely candidate for a role in the 

process, however, was extracellular signal-regulated kinase 

(ERK). This enzyme is 

known both to foster 

the new cellular connections that register 

emotional and object 

recognition memories 

in the brain and to be 

affected by cocaine.

The researchers 

explored ERK’s role in 

a behavior called 

conditioned place 

preference (CPP). 

By exhibiting CPP—

lingering in a part of a 

cage where it has had 

a drug experience—

an animal indicates 

that it remembers the 

experience, associates 

it with the preferred 

cage area, and is seeking to have it again 

(for more on CPP, see 

“Animal Experiments 

in Addiction Science,” NIDA Notes, Vol. 20, No. 5). In 

previous research, blocking ERK activity in the nucleus 

accumbens (NAc) prior to exposing rats to drugs prevented 

them from developing CPP. Drs. Miller and Marshall 

reasoned that if blocking ERK forestalls initial formation of the memory links underlying CPP, it might also 

weaken links that had already been formed. The potential 

therapeutic implications would be significant if this were 

so; they would suggest that manipulating ERK might be 

a means to disrupt drug-environment associations that are 

already established by the time patients begin therapy.

To test their hypothesis, the researchers administered 

cocaine to rats daily for 9 days, after which the rats exhibited CPP whenever they were placed back in their test 

cage. The researchers then conducted a series of trials and 

assays that showed:

• CPP involves activation of ERK: Rats that lingered in 

the cocaine-associated area of the test cage had higher 

ERK levels in the core area of the NAc than a group 

of rats that had not been exposed to cocaine or a third 
45

group exposed to cocaine but not 

trained to exhibit CPP.

• Inhibiting ERK activity can block 

retrieval of cocaine-associated memories for 24 hours: The investigators 

infused a compound called U0126, 

which reduces ERK activity, directly 

into the NAc cores of some of the 

CPP-trained rats. When placed in 

the test cage 30 minutes later, these 

rats gravitated to the cocaine-associated area much less consistently than 

did a group of CPP-trained rats that 

were injected with saline rather than 

U0126. Tested again 24 hours later, 

they still exhibited little or no preference for the area.

• Inhibiting ERK activity at the time 

cocaine-associated memories are 

retrieved can make them unavailable 

for subsequent retrieval for at least 2 

weeks: Rats were placed in the test 

cage and given U0126 immediately 

after exhibiting CPP. When retested 

the following day, they showed no 

partiality to the drug-associated 

cage area, nor did a similarly treated 

group of animals tested 2 weeks 

later. “These animals had effectively 

recollected their cocaine experience 

on day 1, but on day 2 and even 14 

days later, there was no evidence that 

the memory was active,” Dr. Miller 

notes.

“This last observation provides powerful 

evidence that disruption of ERK activity blocks memory reconsolidation,” 

Dr. Miller says. “Memories are unstable 

during the interval between being 

recalled and being refiled, and, if the 

reconsolidation process is disrupted, the 

memory can be lost. The animals behave 

as though it had never been formed 

to begin with. The fact that powerful 

memories associated with drugs may 

become pliant and susceptible to disruption by ERK inhibition during reconsolidation suggests 

opportunities for new therapies.” For example, pending 

much further research, it is conceivable that an approach 

combining exposure to a cue with administration of an 

ERK inhibitor might prevent a patient from reconsolidating—and thus erase—the memory chain linking the cue 

to craving.

“This research provides important new understanding of 

the processes that take place when the brain is manipulating memories, and it identifies specific molecules that help 

shape those processes,” comments Dr. Jerry Frankenheim 

of NIDA’s Division of Basic Neuroscience and Behavioral 

Research. “The fact that the intervention with U0126 

came after the animals had already learned the cocaineplace association may be important for translating this 

Groundbreaking research on the molecular basis of long-term 

memory could open a new path to the treatment of drug addiction, post-traumatic stress disorder (PTSD), and other conditions in which memories exert a powerful influence on behavior, 

according to neuroscientists who presented research at a NIDA 

conference, “Frontiers in Addiction Research.” Their findings suggest that when long-term memories are recalled, they return to a 

state in which they can be altered or erased before undergoing 

“reconsolidation” for future potential use. This discovery could 

lead to the development of medications that disrupt the reconsolidation process and thereby prevent memories associated with 

drug abuse or trauma from being reestablished.

Dr. Karim Nader of McGill University in Montreal, Canada, 

explained the process of reconsolidation and how interventions 

based on that process might work. The goal, he said, is not to 

simply erase memory, but rather to modulate the memory so that 

its effects are more manageable in conditions such as PTSD or 

addiction. “Our research shows that when a consolidated longterm memory is reactivated, it returns to a labile state similar to 

short-term memory. Neurons must synthesize new proteins in 

order for the memory to persist. If protein synthesis is inhibited 

after reactivation, reconsolidation can’t occur,” he said.

Although he cautioned that there is an enormous amount of work 

to be done before testing the effect in human patients, Dr. Nader 

said his animal studies have significant clinical implications. “In 

the case of drug addiction, if drug-related memories could be 

reactivated and prevented from being restored, drug-seeking 

behavior could in principle be greatly reduced in one session,” he 

said. “It sounds like science fiction, but it is not.”

Dr. Susan Volman of NIDA’s Division of Basic Neuroscience and 

Behavioral Research and Dr. Barbara Sorg from Washington 

State University cochaired the session on “Reconsolidation of 

Memory: A New Approach to Treat Drug Addiction?” at the conference, which was held in Washington, D.C., November 11, 

2005, in conjunction with the annual meeting of the Society for 

Neuroscience. 

New Findings on Memory Have Implications 

For Treatment
46

research to possible clinical application. There are many ways to block the 

initial consolidation of memory, but 

the approach used in this research—

interrupting reconsolidation—is much 

more relevant to intervening in cocaine 

abuse,” he adds. 

Source

• Miller, C.A., and Marshall, J.F. 

Molecular substrates for retrieval 

and reconsolidation of cocaine-associated contextual memory. Neuron

47(6):873-884, 2005. 

NIDA-sponsored researchers at Mount Sinai School of Medicine, 

New York, have found another way to break the chain of molecular events that binds drug-taking to a familiar environment: inhibiting protein synthesis. Earlier research established that genedirected protein manufacture is necessary to stabilize a new 

memory and that blocking this molecular process can keep lasting memories from being formed and even disrupt an established 

memory.

The Mount Sinai researchers, led by Dr. Cristina Alberini, performed experiments similar to those done by Drs. Miller and 

Marshall, but exposed the rats to morphine rather than cocaine 

and used chemicals that blocked protein synthesis rather than 

ERK. Like ERK inhibition, the protein blocker weakened conditioned place preference, but it did so only when given in close 

conjunction with an actual morphine administration.

Unlike the ERK inhibition technique used by the UC researchers, 

“blocking protein synthesis only worked after a repeat of the full 

experience,” says Dr. Susan Volman of NIDA’s Division of Basic 

Neuroscience and Behavioral Research. But the take-home message is the same: “It is possible to disrupt the strong association 

between a drug and place cues.”

The chemicals used in this experiment inhibit protein synthesis in 

general, and it will take a lot more research to develop pharmacotherapy that goes after specific proteins and molecular pathways involved in CPP, Dr. Volman says. But potential applications, she suggests, might go beyond the addiction-environment 

link: “If we can use protein synthesis inhibition to uncouple place 

from relapse, perhaps we’ll ultimately be able to uncouple cues 

like paraphernalia, or even the memory of the drug experience.” 

Source

Milekic, M.H., et al. Persistent disruption of an established morphine conditioned place preference. Journal of Neuroscience

26(11):3010-3020, 2006.

Blocking Protein Also Stops 

Drug-Linked Memory
Research Findings

47

Volume 20, Number 5 (April 2006)

Nicotine and Cocaine Vaccines Move Forward

Nicotine: A vaccine to prevent nicotine addiction demonstrated a good safety profile in a recent clinical trial with 

68 healthy smokers. Dr. Dorothy Hatsukami of the University of Minnesota and colleagues found NicVAX to be safe 

and well tolerated, with side effects comparable to those of placebo. Overall, the reported side effects—most commonly 

general discomfort, headache, and muscle pain—were mild to moderate in severity. The vaccine triggers the production 

of antibodies that bind nicotine in the blood and keep it from reaching the brain. Nevertheless, healthy smokers who 

received the vaccine did not experience craving or withdrawal symptoms, nor did they increase the number of cigarettes 

smoked during a 38-week study and followup. 

Source

• Pharmacodynamics and Drug Action 78(5):456-467, 2005. 

COCAINE: An investigational medication designed to induce the body’s natural defenses to inactivate cocaine before 

it reaches the brain has cleared an important human trials hurdle. Dr. Bridget Martell, Dr. Thomas Kosten, and their 

colleagues at Yale University tested the compound, now designated TA-CD, in an open-label study involving 18 cocaineaddicted participants who took it for either 8 or 12 weeks. No participant reported adverse effects, and all still had 

cocaine-specific antibodies in their bloodstream 6 months after their first injection. At the 6-month followup, participants reported exposure to the drug produced only mild euphoric effects, even though blood tests showed waning concentrations of the antibodies.

Source

• Biological Psychiatry 58(2):158-164, 2005. 
Research Findings

48

Cocaine Abuse and HIV Are Linked With Coronary Calcification

Cardiovascular changes that are potential risk factors for serious heart disease are detected in relatively 

young people with HIV infection or a history of cocaine abuse.

By Lori Whitten, NIDA Notes Staff Writer

Volume 20, Number 5 (April 2006)

Cocaine abuse and HIV infection each raise the likelihood that calcium deposits will form in coronary arteries, 

according to a NIDA-supported study. The findings, by 

Dr. Shenghan Lai and colleagues at The Johns Hopkins 

University, suggest that individuals with either problem 

may develop elevated risks for serious, potentially fatal 

heart disease. The gradual buildup of calcium deposits and 

fat along the inner walls of blood vessels produces atherosclerosis, the narrowing and obstruction of the vessels that 

is a major cause of strokes and heart attacks. Although 

none of the participants in the study had a clinical heart 

problem, all were relatively young to have coronary 

calcification.

Dr. Lai and his colleagues used cardiac computed tomography (CT) scanning to detect the presence of coronary 

calcification and the number, size, and volume of calcium 

deposits in 192 African-American men and women aged 

25 to 45. Thirty-two of the participants did not have HIV 

infection and had never abused cocaine (HIV-/cocaine-), 

28 had the infection and were nonabusers (HIV+/cocaine-), 

47 did not have the infection and had abused cocaine 

(HIV-/cocaine+), and 85 had both conditions (HIV+/

cocaine+). About two-thirds were men.

The results revealed coronary calcification in almost onethird (31 percent) of the participants. The prevalence was 

twice as high in the HIV+/cocaine+ group (38 percent) as 

in the HIV-/cocaine- group (19 percent). In the other two 

groups, the proportion of participants with the condition 

fell in between, with 29 percent of the HIV+/cocaine- and 

30 percent of the HIV-/cocaine+ groups showing coronary calcification (see chart). In the U.S. population as a 

whole, the prevalence of coronary calcification among 25- 

to 45-year-olds is about 18 percent.

Participants with HIV infection and/or a history of 

cocaine abuse had more calcium deposits and a greater 

volume of calcification than nonabusers without the infection. Compared with the HIV-/cocaine- group, the total 

volume of coronary calcium 

was 2.9 times 

as high in the 

HIV+/cocainegroup, 2.6 times 

as high in the 

HIV-/cocaine+ 

group, and 3.5 

times as high in 

the HIV+/

cocaine+ group. 

The associations 

held when the 

researchers took 

into account 

cardiovascular 

disease risk 

factors, includ-

“Coronary calcification among people at such a young age is a striking 

observation and suggests that clinicians should monitor heart disease 

in these populations, advise patients 

to make lifestyle changes, and perhaps treat conditions that affect heart 

health, such as high blood pressure.”
49

ing age, body mass index, lipid levels, blood pressure, and 

whether patients were taking HIV medication. The study 

was too small to determine whether HIV and cocaine contribute independently to calcification when both are present, or whether they interact physiologically to promote it 

even more.

Cardiovascular complications have been well documented 

in patients who abuse cocaine and also have HIV infection, but this study is the first to show arterial changes 

prior to the development of cardiovascular symptoms and 

to link them with cocaine abuse alone and HIV infection alone. Larger, longer studies are needed to confirm 

Dr. Lai’s associations and to determine whether or how 

cocaine- and HIV-associated calcification progresses to 

clinical atherosclerosis and heart disease.

Dr. Jag Khalsa of NIDA’s Division of Pharmacotherapies 

and Medical Consequences of Drug Abuse says early 

signs of cardiovascular disease should be taken very seriously because they are strongly connected to two major 

causes of death—stroke and heart attacks. “Coronary 

calcification among people at such a young age is a striking observation and suggests that clinicians should monitor heart disease in these populations, advise patients to 

make lifestyle changes, and perhaps treat conditions that 

affect heart health, such as high blood pressure,” says Dr. 

Khalsa.

Source

• Lai, S., et al. Human immunodeficiency virus 1 infection, cocaine, and coronary calcification. Archives of 

Internal Medicine 165(6):690-695, 2005. 
Research Findings

50

Volume 20, Number 3 (October 2005)

Modafinil Improves Behavioral Therapy Results In 

Cocaine Addiction

By Patrick Zickler, NIDA NOTES Staff Writer

NIDA-supported researchers 

evaluating modafinil’s potential to 

enhance behavioral treatment for 

cocaine addiction have reported a 

second successful clinical efficacy 

trial. The new results affirm and 

extend the promising findings of 

the earlier, smaller, and less stringent “open label” trial, and they set 

the stage for large-scale multisite 

trials that could definitively establish 

the medication’s usefulness.

Dr. Charles Dackis and colleagues 

at the University of Pennsylvania 

Treatment Research Center 

recruited 62 individuals (44 male, 

18 female; mean age, 44.5 years) 

for their double-blind study. All 

had come to the Center seeking 

treatment for cocaine addiction, 

had ingested at least $200 worth 

of cocaine in the 30 days prior to 

presenting for treatment, and met 

the cocaine-dependence criteria of 

the Diagnostic and Statistical Manual 

of Mental Disorders, 4th Edition

(DSM-IV). The patients agreed to visit the clinic twice a 

week for individual sessions of cognitive-behavioral therapy 

(CBT) and provide urine samples 3 times a week for the 

8-week course of the study. Once each week, the clinic 

staff dispensed a week’s supply of pills, either modafinil in 

daily doses of four 100 mg pills (30 patients) or an equal 

number of identical-looking placebo pills (32 patients).

Throughout the study, modafinil-treated patients gave 

fewer cocaine-positive urine samples than the placebo 

group. “More impressive, though, is the fact that more 

than twice as many modafinil patients as placebo patients 

(33 percent compared with 13 percent) were able to 

attain abstinence for 3 weeks or more,” Dr. Dackis says. 

“Maintaining abstinence for a prolonged period during 

treatment is an important clinical threshold. Cocaine is a 

binge drug, and it is common in outpatient treatment for 

a patient to go 4 or 5 days without using, relapse, then 

have another clean week. The long continuous abstinence 

we saw with modafinil is a strong and encouraging signal 

that this medication can help patients avoid relapse during the critical first weeks of treatment.” Both groups of 

patients attended the same average number of CBT 

sessions, he adds, further supporting the likelihood that 

modafinil was the factor accounting for reduced cocaine 

abuse in those who received it.

Modafinil, a medication currently used to treat narcolepsy, 

enhances levels of glutamate, a chemical that influences the 

activity of cells throughout the brain. Animal research has 

shown that repeated exposure to cocaine depletes glutamate levels in brain regions associated with development of 

dependence and addiction, and that increasing glutamate 

concentrations will block reinstatement of cocaine selfadministration in rats—a model of relapse to drug abuse 

in humans (see “Brain Glutamate Concentrations Affect 

Cocaine Seeking,” NIDA NOTES, Vol. 19, No. 3, p. 1).

Combining Modafinil with Behavioral Therapy in Cocaine 

Addiction Treatment Increases Likelihood of Abstinence 

Abstinence rates among patients who received modafinil plus behavioral therapy during 

8-week cocaine addiction treatment were consistently higher than rates among patients 

who received placebo. 
51

Modafinil’s modulation of glutamate transmission may 

account for a striking effect reported by patients: “The 

mechanism for this isn’t clear, but some patients receiving 

modafinil told us that if they did use cocaine it did not 

produce the irresistible urge to use more, which they had 

always felt before,” Dr. Dackis says. “Some of the patients 

told me they had flushed cocaine away. In 25 years of 

treating addiction, no one ever told me they threw away 

cocaine.” 

“The body of research suggesting that modafinil is effective in treating cocaine addiction is growing,” says Dr. 

Ivan Montoya of NIDA’s Division of Pharmacotherapies 

and Medical Consequences of Drug Abuse. “Animal 

research supports the assumption that modafinil reverses 

the cocaine-induced neurochemical disruptions of glutamate and of dopamine-containing neurons in the brain’s 

reward centers. Clinically, modafinil has effects that are 

opposite to the symptoms of cocaine withdrawal, which 

usually include oversleeping, depression, poor concentration, and craving.”

Dr. Dackis and his colleagues are now planning the next 

test for modafinil: a multisite clinical trial that will include 

more than 650 participants. The study will evaluate 

modafinil’s efficacy in doses of 200 mg and 400 mg per 

day in combination with CBT, and results may be available by mid-2006, Dr. Montoya says. 

Source

• Dackis, C.A., et al. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. 

Neuropsychopharmacology 30(1):205–211, 2005. 
Research Findings

52

Disulfiram Reduces Cocaine Abuse

By Lori Whitten, NIDA NOTES Staff Writer

Volume 20, Number 2 (August 2005)

Disulfiram, a well-established medication 

for the treatment of alcoholism, has helped 

people addicted to cocaine reduce abuse of 

the drug from 2.5 days a week to 0.5 days 

a week on average. The finding builds on 

previous studies in which NIDA-funded 

researchers demonstrated the medication’s promise in two subgroups of cocaine 

abusers—alcoholics and those with cooccurring opioid addiction. Their current 

results suggest that disulfiram is effective in treating the general population of 

cocaine-addicted patients, including those 

who are nonalcoholic. The medication’s 

effectiveness in nonalcoholic patients adds 

to evidence that disulfiram works directly 

to reduce cocaine abuse rather than indirectly by reducing concurrent alcohol 

abuse. The investigators also found that, 

like disulfiram, cognitive-behavioral 

therapy (CBT) reduced cocaine abuse by 

2 days.

Dr. Kathleen Carroll and her colleagues 

at Yale University School of Medicine in 

New Haven, Connecticut, treated 121 

outpatients for 12 weeks. The 32 women 

and 89 men met the criteria for cocaine 

dependence specified in the Diagnostic and 

Statistical Manual of Mental Disorders, 4th 

Edition

(DSM-IV) and reported abusing cocaine 13 days on 

average during the month and 2.5 days during the week 

before treatment. During the study, each patient received 

either 250 mg/day of disulfiram or placebo and participated 

in weekly individual sessions of behavioral therapy, either 

CBT or IPT (interpersonal psychotherapy). CBT coaches 

patients to recognize and cope with situations that tend 

to induce drug craving and abuse. In IPT, patients clarify 

and address key personal problems related to the substance 

abuse. On average, patients attended eight behavioral 

therapy sessions. The type of therapy did not affect rates 

of treatment completion. 

All patients abused cocaine on fewer days during treatment than they had in the weeks before. The extent of 

recovery depended on the therapy. By the end of treatment, patients taking disulfiram reduced weekly cocaine 

abuse by 2 days on average, compared with 1 day for 

those taking the placebo, no matter which psychotherapy 

group they participated in. Similarly, patients who participated in CBT reduced weekly cocaine abuse by 2 days on 

average, compared with 1 day for IPT participants regardless of which medication they received. The data were 

based on self-reported cocaine abuse, but weekly urine 

tests generally corroborated (84 percent) patient information. More urine samples from participants receiving disulfiram and CBT (51 percent), placebo and CBT 

(50 percent), and disulfiram and IPT (44 percent) were 

cocaine negative during the study than those from participants taking the placebo and IPT combination (30 percent); the latter demonstrated the least favorable treatment 

outcomes. 

Dr. Carroll and her colleagues verified compliance with 

the daily medication regimen by testing urine samples for 

tracers that were added to the medication and the placebo. 

Taking the capsules every day was associated with better 

outcomes among patients who received either disulfiram 

Over the 12-week study, patients taking disulfiram or participating in cognitivebehavioral therapy (CBT) demonstrated greater reductions in cocaine abuse than

those taking placebo or receiving interpersonal psychotherapy (IPT).
53

or placebo, although disulfiram’s effectiveness remained 

superior to placebo’s when the researchers took medication compliance into account. Dr. Carroll emphasizes that 

“not taking medication can undercut the benefits of all 

pharmacotherapies, and an important goal of behavioral 

therapy is improvement of medication compliance.” Dr. 

Dorynne Czechowicz of NIDA’s Division of Clinical 

Neuroscience, Development and Behavioral Treatment 

says the findings highlight the importance of integrating addiction medication and behavioral treatment. “All 

patients in the study participated in some form of behavioral therapy, which facilitated recovery from substance 

abuse and helped patients stick to the medication regimen,” she says.

Disulfiram had a more pronounced benefit for patients 

who were not alcohol-dependent at the outset of the study 

and for those who abstained from alcohol during the 

study. Patients who drank while taking disulfiram tended 

to take less of the medication than those who did not 

drink. Instead of deterring drinking and thereby reducing cocaine abuse, the unpleasant physical consequences 

of mixing alcohol with the medication led patients to 

stop taking disulfiram when they wanted to drink or 

abuse cocaine. “These findings seem to validate the clinical observation that patients have to stop drinking before 

they can kick cocaine abuse,” says Dr. Carroll. Patients 

participating in CBT showed better outcomes than those 

in IPT, regardless of concurrent drinking. CBT, a wellestablished behavioral treatment, might be the best option 

for some patients, including those facing co-occurring 

alcohol and cocaine addiction, she says. Patients without 

concurrent alcoholism may be candidates for disulfiram, 

CBT, or a combination. 

Disulfiram interacts with cocaine to produce an unpleasant sense of hyperstimulation. In laboratory studies, 

people experiencing a disulfiram-cocaine interaction 

demonstrated increased heart rate and blood pressure 

and reported anxiety, paranoia, and restlessness. Animal 

studies suggest that disulfiram, like cocaine, enhances the 

activity of the neurotransmitter dopamine. Possibly, when 

someone has taken disulfiram, subsequent administration 

of cocaine elevates dopamine to excessive levels that produce discomfort and aversion.

Animal research suggests that disulfiram increases levels of 

dopamine by blocking an enzyme that breaks dopamine 

down. People with low levels of the enzyme, dopamineb-hydroxylase (DBH), have increased dopamine activity. 

Hormones, as well as genes, may influence DBH levels. Researchers suspect that estrogen hormones increase 

DBH, attenuating the effect of disulfiram, which could 

explain why women seem to benefit less than men.

Source

• Carroll, K.M., et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: A randomized placebo-controlled trial. Archives 

of General Psychiatry 61(3):264-272, 2004. 
54

Researchers studying disulfiram, an “old” medication for alcoholism that has emerged as a potential “new” 

treatment for cocaine abuse, have found a possible sex difference in treatment response: Cocaine-addicted 

men who were treated with the medication had better outcomes than those who were not, whereas women 

showed no significant difference in outcome.

Dr. Kathleen Carroll of Yale University School of Medicine and her colleagues have conducted several 

studies on the medication’s effects on cocaine abuse and have moved on to the next step—determining 

which types of patients benefit from the treatment. There were not enough women in their recent study (see 

“Disulfiram Reduces Cocaine Abuse”) to analyze sex differences, so the investigators combined data from 

two of their other treatment studies to compare men’s and women’s responses to disulfiram. “We know that 

men and women react to cocaine differently. For example, women progress more quickly to cocaine addiction than men. Sex differences in treatment response seemed likely,” says Ms. Charla Nich, lead investigator 

of the study. 

In one study, the investigators treated alcohol- and cocaine-addicted patients with disulfiram and various 

behavioral therapies; in the second, they tested disulfiram in opioid- and cocaine-addicted patients under 

treatment with methadone. Altogether, 191 patients participated in the studies, which, when combined, had 

enough women (36 percent) to permit a valid comparison.

Both studies found that patient groups taking disulfiram reduced cocaine abuse compared with groups 

receiving placebo. But when the investigators combined and reanalyzed the data, they found that only the 

men in the groups responded to the medication. The reanalysis indicated that men treated with disulfiram 

produced a higher percentage of drug-free urine specimens than men in the placebo groups (49 versus 30 

percent). Among women, however, the percentage of drug-free specimens was not significantly different 

with disulfiram or placebo (38 versus 39 percent).

“Our data don’t conclusively prove a sex difference in the response to disulfiram,” says Ms. Nich. “For 

that, we need studies that directly compare men and women taking the medication.” NIDA’s Dr. Dorynne 

Czechowicz agrees that researchers should follow up on these intriguing preliminary findings, which “highlight the importance of paying attention to sex differences in medication development and other drug abuse 

research.”

Source: Nich, C., et al. Sex differences in cocaine-dependent individuals’ response to disulfiram treatment. 

Addictive Behaviors 29(6):1123-1128, 2004. 

Disulfiram May Work for Men, but Not Women
Research Findings

55

Genetic Engineering Reveals Proteins’ Key Role in 

Sensitivity to Cocaine

Volume 20, Number 2 (August 2005)

Genetic engineering strategies like those used at the 

California Institute of Technology to study nicotine 

addiction have helped other investigators identify a pair of 

proteins that seem to influence cocaine addiction. 

Dr. Peter Kalivas and his colleagues at the Medical 

University of South Carolina in Charleston developed 

a strain of mice lacking two genes, called Homer1 and 

Homer2, that direct production of proteins linked to 

cocaine’s effects in the brain. The researchers found that 

the Homer “knock-out” mice were more sensitive than 

unmodified mice to the behavioral effects of cocaine. 

Compared with unmodified mice, animals missing either 

Homer1 or Homer2 developed stronger place conditioning—when allowed to move freely, they would spend 

more time in a compartment where they had received 

cocaine than in a compartment with no drug association. 

The knock-out mice also were more sensitive to cocaine’s 

stimulatory effect; when placed in a chamber equipped 

with photoelectric beams that could measure activity, the 

knock-outs were approximately 50 percent more active 

than unmodified mice following cocaine injections. To 

verify the role of the Homer genes in increased sensitivity 

to cocaine, the researchers restored Homer genes in the 

brains of the knock-outs, eliminating the previously seen 

differences in stimulation and place conditioning.

“The fact that Homer deletions result in these augmented 

responses to cocaine suggests that disruption of Homer

protein-regulated signaling in the brain is a central step 

in development of cocaine addiction,” Dr. Kalivas says. 

Additional evidence of this role is seen in changes that 

Homer deletion causes in levels of the brain messenger 

chemical glutamate, he adds. Homer knock-out mice that 

had never been exposed to cocaine had nucleus accumbens 

(NAc) glutamate concentrations about 50 percent lower 

than mice with the genes—an effect similar to that seen 

in mice after cocaine withdrawal. This effect, too, was 

reversed when the scientists injected Homer genes into the 

NAc. 

The association between Homer activity and the conditions of cocaine withdrawal is particularly intriguing, 

according to Dr. Kalivas, because other researchers have 

shown that Homer protein levels rise and fall in response 

to environmental cues and changing levels of stress. 

“Homer may be a window to study the molecular basis 

of the important link between environmental stress and 

cocaine addiction.”

Source 

• Szumlinski, K.K., et al. Homer proteins regulate sensitivity to cocaine. Neuron 43(3):401-413, 2004. 
Research Findings

56

Researchers Investigate Cocaine “Abstinence Syndrome”

By Lori Whitten, NIDA NOTES Staff Writer

Volume 20, Number 1 (August 2005)

Researchers have long focused on motivation as the centerpiece of the addiction puzzle, based on the observation 

that in many addicted individuals, compulsive drugseeking behavior overtakes the most fundamental motivators, including food and sex. Now, however, researchers 

are beginning to examine another aspect of addictive 

drugs—their powerful and long-lasting effects on mood. 

People who have recently stopped abusing stimulant drugs 

commonly experience “abstinence syndrome”: low energy, 

irritability, restlessness, an inability to feel pleasure, and 

problems with concentration. Anxiety and panic attacks 

also are sometimes associated with cocaine abstinence. 

Addiction researchers are examining the neurobiology 

underlying abstinence syndrome with an eye toward 

improving current therapies’ ability to alleviate these 

symptoms and prevent relapse.

NIDA investigators concentrated recently on the impact 

of cocaine on the neurotransmitter norepinephrine (NE), 

one of the two neurochemicals most responsible for 

mood. Stimulation of brain cells by serotonin and NE is 

central to positive mood, feeling energetic, and maintaining focus as well as sleep, appetite, and coping with stress. 

Two recent animal studies, one conducted by investigators at NIDA’s Intramural Research Program (IRP) in 

Baltimore and another by NIDA-funded researchers at 

Harvard Medical School’s New England Primate Research 

Center in Southborough, Massachusetts, suggest that 

cocaine may compromise NE’s ability to stimulate brain 

cells by altering a communication protein, called the

a2-adrenergic receptor, on the surfaces of the cells.

In the Baltimore study, Dr. Michael Baumann and colleagues hypothesized that by giving rats cocaine regularly—twice-daily injections at 15 mg/kg of the animals’ 

body weight for 7 days—and then abruptly stopping it, 

they would reduce the a2-adrenergic receptors’ responsiveness. To assess the adrenergic system in the cocaineexposed, now “abstinent” rats, the researchers used the 

clonidine challenge procedure, which indirectly indicates 

a2-adrenergic receptor activity by measuring how much 

plasma levels of growth hormone (GH) increase following 

exposure to the drug clonidine (see “Clonidine Challenge 

Test Results Suggests That Cocaine Abuse Desensitizes 

Adrenergic System”). Confirming the researchers’ hypothesis, the cocaine-exposed animals showed a blunted 

GH response—less than half that of saline-exposed animals—15 and 30 minutes after the clonidine challenge. 

The rats’ response was still low, but returning toward 

Clonidine elevates growth hormone (GH) secretion in rats, a

response mediated through the a2-adrenoreceptors in the brain. 

When rats are exposed to repeated cocaine injections, GH secretion 

in response to clonidine is lowered. The clonidine challenge test is 

used to measure a2-adrenoreceptor sensitivity in humans as well as 

animals.
57

normal, when the researchers repeated the challenge procedure 8 days after daily injections stopped. 

The findings suggest that cocaine consumption and 

cessation may lower recovering individuals’ moods by 

desensitizating the a2-adrenoreceptors, but the results 

are preliminary. “The adrenergic system is complex, 

with multiple pathways in the brain and body,” says Dr. 

Baumann. “We still have much to learn about how drug 

exposure affects all these pathways, how it affects serotonin, and how they both influence growth hormone.” 

People with depression secrete less GH in response to the 

clonidine challenge than do those without 

the condition, a clinical finding that suggests possible links between NE receptor 

function, mood disorders, and cocaine 

withdrawal. “Although investigators are 

only beginning to characterize norepinephrine’s role in addiction, a growing 

body of animal and clinical research suggests important connections between the 

adrenergic system, mood and anxiety disorders, and the depression-like symptoms 

experienced by people trying to overcome 

cocaine addiction,” Dr. Baumann says. 

A Role in Relapse?

In a study that explored the chemical basis of mood 

and cocaine relapse, Dr. Roger Spealman and colleagues 

hypothesized that blocking a2-adrenergic receptors in 

monkeys would generate anxiety and induce a resumption 

of previously extinguished cocaine-seeking behavior. 

The researchers trained monkeys to seek cocaine by pressing a lever. When the monkeys reached a high rate of 

lever pressing, the researchers disconnected it from the 

injection device. The monkeys kept trying the lever for a 

while, but with no more cocaine forthcoming, gradually 

left off. The investigators hypothesized that giving monkeys a drug to reduce NE activity would make the animals 

anxious, and the anxiety would intensify their urge for 

cocaine to the point where they would resume pressing 

the lever despite recent experience of its futility.

Dr. Spealman and colleagues gave the now “abstinent” 

animals various doses of two a2-adrenergic blocking 

agents, yohimbine and RS-79948, in separate test sessions. 

Both a2-adrenergic receptor blockers set the animals to 

pressing the lever again. The increase ranged from 1.5 to 

4 times the response to injections of sterile water, depending on the dose and drug. The yohimbine injections also 

increased physiological and behavioral signs of anxiety: 

salivary cortisol levels and self-grooming and scratching.

To confirm that yohimbine’s behavioral effects were 

due to its inhibition of the a2-adrenergic system, rather 

than any of the other neurotransmitter systems this agent 

affects, the researchers conducted further experiments. 

First, they gave the monkeys yohimbine plus clonidine, 

a drug that selectively blocks yohimbine’s effects on the 

a2-adrenergic receptors. With this regimen, the animals 

resumed lever pressing hardly or not at all. Next, the 

researchers gave the monkeys yohimbine plus flupenthixol, 

a drug that reduces dopamine activity and has no effect on 

yohimbine’s inhibition of a2-adrenergic activity. Under 

this regimen, the animals did resume lever pressing. Both 

of these findings pointed to a2-adrenergic suppression 

as the key to yohimbine’s effects in the first experiment. 

Yohimbine did not stimulate movement or make the 

animals restless, which indicates 

that it worked by blocking receptors, not simply by mimicking the 

stimulant effects of cocaine. 

“It makes sense physiologically 

that the adrenergic system might 

play a role in addiction; cocaine 

activates norepinephrine as much 

as it stimulates dopamine,” says 

Dr. Spealman. Work by others 

suggests that cocaine abuse leads 

to long-term desensitization of the 

NE system in areas of the brain 

involved in reward and stressinduced reinstatement of drugseeking. “This has led some researchers to speculate that 

the desensitized adrenergic system increases vulnerability 

to further norepinephrine disturbances—for example, 

those caused by stress or drug re-exposure—which may 

increase relapse risk,” explains Dr. Spealman. 

Researchers continue to seek to unravel the complexities 

underlying withdrawal and relapse to drug-taking. If, as 

scientists now think, these phenomena arise from sequential alterations in both the reward and mood pathways, 

“addiction medications may have to target different neurotransmitters at various stages of abstinence,” says Dr. 

Minda Lynch of NIDA’s Division of Basic Neurosciences 

and Behavior Research. 

Sources

• Baumann, M.H.; Milchanowski, A.B.; and Rothman, 

R.B. Evidence for alterations in a2-adrenergic receptor sensitivity in rats exposed to repeated cocaine 

administration. Neuroscience 125(3):683-690, 2004.

• Lee, B.; Tiefenbacher, S.; Platt, D.M.; and Spealman, 

R.D. Pharmacological blockade of a2-adrenoreceptors 

induces reinstatement of cocaine-seeking behavior in 

squirrel monkeys. Neuropsychopharmacology 

29(4):686-693, 2004. 

“It makes sense 

physiologically that the 

adrenergic system might 

play a role in addiction; 

cocaine activates 

norepinephrine as much as 

it stimulates dopamine.”
Research Findings

58

Cocaine-Related Environmental Cues Elicit Physiological Stress 

Responses

By Lori Whitten, NIDA NOTES Staff Writer

Volume 20, Number 1 (August 2005)

Overcoming addiction is in part a learning process, and 

people in recovery work to make and maintain healthy 

changes. In behavioral therapy, clinicians help patients 

learn techniques to avoid or navigate safely through 

experiences that evoke powerful urges to consume drugs: 

stressful situations and the people, places, and things 

the patient associates with past drug-taking experiences. 

Recent NIDA-funded research has demonstrated that 

cocaine-addicted patients respond to these drug-associated 

features in the environment as if they were stressful situations, with the release of adrenaline and other hormones 

that increase pulse rate and blood pressure, among other 

effects. The investigators also found that these responses 

of cocaine abusers take a long time to normalize, perhaps 

indicating that the drug heightens sensitivity to stress.

Dr. Rajita Sinha and colleagues at the Yale University 

School of Medicine in New Haven, Connecticut, conducted their study with 54 cocaine-addicted men and 

women, aged 21 to 50, at an inpatient research facility. 

Before entering treatment, the patients had abused cocaine 

for an average of 9 years; immediately prior to treatment, 

they had, on average, consumed the drug 3 or more times 

per week and spent $224 weekly to buy the drug. Almost 

all (94 percent) consumed cocaine in its smoked form 

(crack). Each patient had been abstinent for 2 weeks prior 

to the laboratory sessions.

To study physiological and emotional responses to stress 

and cocaine-related cues in the laboratory, the investigators drew on the patients’ individual experiences. They 

elicited from each patient detailed accounts of three past 

personal experiences: one very stressful, one relaxing, 

and one specifically related to taking cocaine. From each 

patient’s stories, the researchers created three tape recordings that would, when played back, rekindle his or her 

feelings of stress, relaxation, and cue-induced craving (see 

“Reliving A Stressful Situation: Excerpt From a Guided 

Imagery Tape”). To enhance the strength of the responses, 

the researchers trained the patients in guided imagery—

how to relive a scene mentally while listening to a tape, as 

if it were happening at that moment. 

Each patient participated in three 3-hour testing sessions. 

Throughout each session, the patient sat on a hospital bed 

wearing headphones, an intravenous catheter in one arm 

for drawing blood, a blood pressure monitor on the other 

arm, and a pulse sensor on one finger. For the first hour, 

an adaptation period, the patient practiced tape-guided 

progressive relaxation while periodically reporting anxiety and craving levels. Next, the patient heard one of the 

5-minute tapes based on his or her own experiences, introduced with a message to “Close your eyes and imagine 

yourself in the following situation.” Over the three testing 

sessions, conducted on different days, the patient relived 

all three of his or her stressful, drug-related, and relaxing 

experiences. When the tape finished, the patient rated the 

vividness of the scenes and his or her cocaine craving and 

anxiety. A nurse monitored the patient’s pulse and blood 

pressure and drew blood samples periodically during the 

testing and for 75 minutes after the tape ended. 

The researchers found similar responses to the stressful 

and drug-related tapes. Patients’ pulses increased and their 

blood pressure rose while they listened to both. Blood 

levels of biochemicals involved in the stress response—

including noradrenaline, cortisol, prolactin, adrenocorticotropic hormone, and adrenaline—were elevated when 

Cortisol levels, which normally decline in the morning, remain

relatively high in cocaine-addicted patients after they listen to a 

five-minute tape of a stressful or drug-related experience, but not 

after they listen to a relaxing tape. Cue-induced elevations in

cortisol and other stress hormones persisted for up to 30 minutes.
59

participants listened to stressful and drug-related tapes 

compared with when they listened to the relaxing tapes. 

Stressful and drug-related tapes also increased participants’ 

subjective responses—craving and anxiety—compared 

with the relaxing tapes. 

The stress responses generated in the study were in keeping with previous laboratory studies with cocaine abusers, 

says Dr. Sinha. “Stress reactions after both the stressful 

and drug-related tapes in this study were similar to or 

higher than those observed when researchers have used 

other techniques to induce stress—for example, requiring 

participants to prepare and give a speech in 5 minutes.” 

Stress Response Persists

Normally the stress response, including the adrenaline 

rush and increased heart rate, breathing, and blood pressure, returns quickly to normal once a threat has passed. 

“What was different and striking in our patients was that 

they continued to show stress after the tape was over—

up to 30 minutes longer than would be expected,” says 

Dr. Sinha. The results suggest that cocaine abusers’ stress 

responses may take longer to normalize, perhaps indicating a heightened reactivity to stress. 

Dr. Sinha and her colleagues are following up with 

patients in this study to determine whether those with 

more intense biological reactions and craving in response 

Cocaine-addicted patients showed greater arousal and increased pulse and biochemical stress response, as well as increased

craving and anxiety, when they mentally relived a 5-minute stressful or drug-related personal experience than when they

listened to relaxation tapes. Arousal persisted for up to 30 minutes after the imagery stopped.
60

to the tapes are more likely to relapse. Similarly, they are 

using brain-imaging technology to determine whether 

neural activation after patients listen to stressful and 

cocaine-related tapes predicts relapse. In addition, to 

determine whether drug abuse is related to a heightened 

stress response, Dr. Sinha is planning studies that compare 

the stress reactivity of addicted and nonaddicted people. 

“Understanding the effects of chronic drug use on how 

people handle stress—particularly the craving and biological responses that occur after stressful situations—will 

allow us to develop medications that are effective against 

craving induced by drug and stressful environmental 

cues,” says Dr. Harold Gordon of NIDA’s Division of 

Clinical Neuroscience, Development and Behavioral 

Treatment. 

Source

• Sinha, R., et al. Hypothalamic-pituitary-adrenal axis 

and sympatho-adreno-medullary responses during 

stress-induced and drug cue-induced cocaine craving 

states. Psychopharmacology 170(1):62-72, 2003. 

Reliving a Stressful Situation: 

Excerpt From a Guided Imagery 

Tape 

There is a knock on the door. You feel tense all 

over your arms, legs, back, and forehead. “You are 

going to get evicted,” he says. Your heart beats 

faster. You had been paying rent to your boyfriend, 

but he never gave it to them. You feel the butterflies 

in your stomach. You have no place to go. “The 

second notice will be here in a couple of days,” he 

is saying, but your mind is racing. You feel shaky 

all over. “What am I going to do? Where will I go?” 

you say. You have cramps in your stomach. You 

grit your teeth and call your mother. She has no 

money to help you. You’ve run out of options. There 

is a deep intense pain inside you and tears come to 

your eyes. 
Research Findings

61

A Single Cocaine “Binge” Can Establish Long-Term Cue-Induced 

Drug-Seeking in Rats

By Lori Whitten, NIDA NOTES Staff Writer

Volume 19, Number 6 (May 2005)

When people abuse a drug, they learn to associate its pleasurable effects with the surroundings in which they experience them. This learning plays a major role in addiction. 

Former drug abusers find that even after years of successful abstinence, they may experience intense cravings upon 

encountering people, places, and things that were present 

during their drug-taking. 

Researchers have been trying to understand how the brain 

forms such associations and how cues 

motivate drug-seeking. Until now, scientists have generally assumed that many 

pairings of drug use and environment are 

needed to establish drug-cue learning, 

but Dr. Friedbert Weiss and his colleagues at The Scripps Research Institute 

in La Jolla, California, recently showed 

otherwise. In a NIDA-funded animal 

study, they demonstrated that rats can 

acquire such long-term learning in the 

space of a single 2-hour session of access 

to cocaine. The rapid formation of drugcue associations seems exceptional; the 

investigators also demonstrated that in 

contrast to cocaine, sweetened condensed 

milk—a food rats find highly palatable—

does not produce persistent effects after a one-time 

exposure.

The investigators chose white noise as the cue they would 

pair with cocaine and then test. To begin, they placed rats 

in a special learning chamber where white noise signaled 

cocaine availability and pressing a lever produced an intravenous infusion of the drug. During a 2-hour session, the 

rats could press the lever freely; the only restriction on 

their cocaine intake was a 20-second time-out after each 

infusion to prevent overdose. On average, each rat pressed 

the lever 43 times.

The researchers hypothesized that during this initial session, the rats learned to seek out the cocaine experience 

and the rats’ brains established a link between white noise 

and the drug experience similar to the environmental cues 

learned by people addicted to cocaine. Their next experimental step would put the rats into a state corresponding 

to abstinence in a former cocaine abuser. To accomplish 

this, they returned the animals to the test cage, now with 

the white noise turned off and the lever disconnected from 

the infusion device. The rats obtained nothing when they 

pressed the lever that previously had delivered cocaine, 

and they gradually gave up. When a rat had pressed the 

lever five or fewer times in three consecutive 1-hour sessions, the researchers concluded that its drug-seeking 

behavior was “extinguished.” The animal’s motivation was 

not strong enough for it to keep pressing a lever that had 

not delivered an infusion in many tries.

In the first two stages of their experiment, 

Dr. Weiss and colleagues had established 

white noise as the sole environmental 

feature in the rats’ experience reliably 

associated with cocaine availability, and 

the rats had ceased drug-seeking (leverpressing) behavior. The investigators were 

now ready to test whether the now “abstinent” rats would respond to white noise 

by reinstating drug-seeking. Immediately 

after the rats abandoned lever-pressing, 

and at 3-month intervals, the researchers returned rats to the test chamber 

and turned on the white noise. The rats 

indeed responded by pressing the lever. 

Moreover, the white noise cue motivated 

the rats to seek cocaine session after session, even though they never received any, for up to an 

entire year. In comparison, a different environmental cue 

associated with saline infusions motivated only a few lever 

presses throughout the experiment.

“Drug-cue learning has a well-known role in craving and 

relapse in addicted individuals,” says Dr. Weiss. “Our 

observations demonstrate that it takes very little experience with cocaine to establish environmental associations 

that become powerful cues for cocaine relapse—and contribute to progression from initial sporadic drug use to 

addiction.”

Food Doesn’t Elicit the Same Cue Response

In a second experiment that demonstrated the unique 

reinforcing power of drugs, Dr. Weiss and colleagues 

showed that a highly palatable food did not produce persistent motivating effects. Following the same procedures 

they used in the cocaine experiment, the investigators 

trained a different group of rats to associate white noise 

with access to sweetened condensed milk (SCM). During 

“...it takes very little 

experience with 

cocaine to establish 

environmental 

associations that 

become powerful 

cues for cocaine 

relapse...”
62

access to SCM, rats 

pressed the lever 

80 times on average. 

Subsequent sessions in 

the test cage extinguished 

the rats’ SCM-seeking. 

The investigators then 

tested white noise’s ability to induce the now 

“abstinent” rats to resume 

pressing the lever. It did 

not, either immediately or 

3 months after extinction. 

The results indicate that a 

“natural” reinforcer does 

not have cocaine’s ability 

to produce a long-lasting 

motivational association in a single session of 

exposure.

“Clearly, an exceptionally strong association is 

established when cocaine 

is paired with a cue,” 

says Dr. Susan Volman 

of NIDA’s Division of 

Basic Neurosciences and 

Behavior Research. “This 

finding is consistent with 

other evidence that drugs 

produce especially rapid 

and long-lasting learning.”

Scientists don’t yet know 

the exact neurobiological mechanisms that form 

learned associations 

from drug experiences. 

However, researchers have observed that drugs induce 

changes in brain cells, or neural adaptations, similar to 

those underlying normal learning. These adaptations 

result in a modification 

of the brain’s neural 

circuitry—the interconnected networks 

of neurons responsible 

for behavioral, cognitive, and emotional and 

motivational processes. 

Dr. Volman explains, 

“Drugs may produce 

such rapid and longlasting learning because 

they have a double effect: They produce intense pleasure 

that reinforces behavior and they enhance neural adaptations at the same time. These brain changes might underlie sustained drug-directed behavior and the ability of cues 

to prompt drug-seeking.” In future studies, Dr. Weiss and 

his colleagues intend to address the physiological mechanisms underlying the different behavioral responses to 

drugs and to natural reinforcers. 

Source

• Ciccocioppo, R.; Martin-Fardon, R.; and Weiss, F. 

Stimuli associated with a single cocaine experience 

elicit long-lasting cocaine seeking. Nature Neuroscience

7(5):1-2, 2004. 

Study Underscores Power of Cocaine Cues to 

Re-Induce Drug-Seeking In Rats

Up to a year after a 2-hour session of free access to cocaine, rats responded more strongly to a cue paired 

with cocaine versus the control, a saline-associated cue. In a second experiment, a 2-hour session of 

free access to a desired food—sweetened condensed milk (SCM)—produced no such long-lasting cue 

responsiveness.

“...an exceptionally 

strong association is 

established when 

cocaine is paired 

with a cue.”
Research Findings

63

Topiramate Shows Promise in Cocaine Addiction

By Lori Whitten, NIDA NOTES Staff Writer

Volume 19, Number 6 (May 2005)

In a small pilot 

study, topiramate—

a medication currently used to treat 

seizure disorders—

has helped cocaineaddicted outpatients 

stay off the drug 

continuously for 

3 weeks or more. 

That may not seem 

like a long time, but 

previous research 

has shown that outpatients who avoid 

relapse for 3 to 4 

weeks during treatment with behavioral therapy and medication have a good 

chance of achieving 

long-term cessation. 

In other clinical trials topiramate has helped prevent relapse to alcohol and 

opiate addiction; these new results with cocaine add to 

hopes that it may prove a versatile treatment medication 

for several drugs of abuse.

Dr. Kyle M. Kampman and colleagues at the University 

of Pennsylvania School of Medicine and the Veteran 

Affairs Medical Center in Philadelphia treated 40 crackcocaine-smoking outpatients, mostly African American 

males, for 13 weeks at the University of Pennsylvania 

Treatment Research Center (TRC). All participants met 

the Diagnostic and Statistical Manual of Mental Disorders, 

4th Edition (DSM-IV) criteria for cocaine dependence. 

They were typical of the chronic, relapsing abusers who 

seek treatment at the TRC: They abused cocaine an average of 10 years, preferring crack to the powder form, and 

demonstrated the average level of drug-related problems. 

However, participants’ abuse was atypical in one way; they 

were on the “milder end of the addiction severity spectrum measured by cocaine withdrawal symptom severity 

and days of abuse and money spent on cocaine,” says Dr. 

Kampman. On average, participants abused cocaine 6 to 

8 days and spent $300 to $500 on the drug in the month 

before treatment compared with the 10 to 13 days and 

$400 to $600 reported by most patients at the facility. 

Because topiramate exacerbates cocaine withdrawal symptoms, the investigators selected patients who were able to 

attain at least 3 days of self-reported abstinence immediately before starting the trial and who, based on their level 

of addiction, were not likely to enter severe withdrawal. 

Dr. Kampman says that about 40 percent of patients 

treated at the TRC experience relatively mild withdrawal 

symptom severity.

After a 1-week baseline period, Dr. Kampman’s team 

gave topiramate to 20 study participants, and placebo to 

the other 20. To avoid potential topiramate side effects, 

including sedation and slurred speech, they initiated treatment with 25 mg/d and increased it by 25 mg/d every 

week to 200 mg/d. They maintained this maximum dose 

during weeks 8 through 12, then tapered to zero during 

week 13. The patients also received cognitive behavioral 

coping skills therapy twice weekly throughout the study. 

The researchers verified cocaine abstinence two times a 

week with urine tests. 

By the end of the 13th week, almost 60 percent of 

patients taking topiramate attained 3 or more weeks of 

continuous abstinence from cocaine compared with 26 

percent of those taking placebo. All 40 patients showed 

improvement from week 1 to week 13, as reflected by 

Topiramate Helps Outpatients Abstain From Cocaine

In almost every week of the study, more patients were abstinent in the topiramate group than in the placebo 

group. Of the 40 participants in the study, more patients taking topiramate achieved 3 or more continuous 

weeks of abstinence from cocaine.
64

lower Addiction Severity Index (ASI) scores. Patients taking the medication improved more, with average scores in 

the topiramate group falling by 69 percent, from 0.210 to 

0.066, compared with 50 percent, from 0.162 to 0.081, 

in the placebo group. Dr. Kampman says the improvement in ASI scores reflects fewer days of cocaine abuse 

and patients’ perceptions of reduced cocaine-related problems. “Patients saw 

the improvement in 

their condition, which 

is an important part 

of recovery,” he says.

“Based on our findings and other work 

showing this medication’s effectiveness as a 

treatment for alcohol 

and opiate addiction, 

topiramate appears 

to have great potential as a relapse prevention medication for people who have achieved initial abstinence from 

cocaine,” says Dr. Kampman. 

Possible Mechanisms

All addictive drugs deliver pleasurable effects by enhancing 

the neurotransmitter dopamine in the mesocorticolimbic 

pathway—areas of the brain involved in reward and motivation. Topiramate seems to change the brain’s response 

to cocaine by indirectly influencing dopamine through 

two other neurotransmitter systems—gamma aminobutyric acid (GABA) and glutamate. Animal studies have suggested to scientists that either activating GABA-producing 

neurons or blocking glutamate receptors would lessen 

craving in cocaine-addicted human subjects. “Topiramate 

does both simultaneously, a unique dual action that 

appears to underlie its promise as a relapse prevention 

medication,” says Dr. Kampman. 

“These are preliminary 

results, but researchers are very excited 

about the potential 

topiramate has shown 

as a treatment for a 

range of problems, 

including addiction 

to several drugs and 

some impulse control 

disorders,” says Dr. 

Frank Vocci, director 

of NIDA’s Division of 

Pharmacotherapies and Medical Consequences of Drug 

Abuse. In addition to its initial successes in preventing 

relapse in patients with alcohol, opiate, and now cocaine 

addiction, animal studies have suggested it may attenuate nicotine addiction. “Topiramate may prove an effective treatment for patients who are addicted to multiple 

drugs,” Dr. Vocci adds.

Dr. Kampman plans additional studies to further evaluate topiramate as a treatment for cocaine addiction. In 

addition to confirming the present results, obtained with 

African American male crack smokers, the medication 

must be tried in other racial groups, women, and powdercocaine abusers. Dr. Kampman and his colleagues also 

plan to study topiramate therapy for patients with coexisting cocaine and alcohol addiction—a group that comprises half of people treated for cocaine abuse.

Source

• Kampman, K.M., et al. A pilot trial of topiramate for 

the treatment of cocaine dependence. Drug and 

Alcohol Dependence 75(3):233-240, 2004. 

“Patients saw the 

improvement in their 

condition, which is 

an important part of 

recovery.”\

“Topiramate may 

prove an effective treatment for 

patients who are 

addicted tomultiple 

drugs.”
Research Findings

65

Volume 19, Number 4 (December 2004)

Men and Women May Process Cocaine Cues Differently

By Lori Whitten, NIDA NOTES Staff Writer 

Some aspects of cocaine addiction and 

recovery are different for men and women—including the reasons for 

seeking drug rehabilitation, response to 

treatment, and vulnerability to relapse. 

Women are more likely to seek cocaine 

abuse treatment in response to cooccurring depression, remain abstinent 

after treatment, and relapse in response 

to interpersonal problems and negative 

feelings. Cocaine-addicted women also 

demonstrate greater craving than men in 

response to drug cues. In the first brain 

imaging study of cocaine craving by 

cocaine-addicted women, NIDA-funded 

researchers have made observations 

that, if borne out in larger studies, may 

point to neurological sources of these 

differences.

Dr. Clinton Kilts and colleagues at the 

Emory School of Medicine in Atlanta 

used positron emission tomography 

(PET) to measure drug-craving-related 

changes in regional cerebral blood 

flow—a correlate of neural activity—in 

eight cocaine-addicted African-American 

women aged 35 to 46. The women had 

abstained from cocaine use for 1 to 14 

days and reported frequent periods of 

cocaine craving in the 30 days preceding 

the study. While lying in the PET scanner, each woman listened to a 1-minute 

recording of a script describing her personal experiences of acquiring the drug and anticipating 

sensations associated with taking cocaine. Each patient’s 

script was derived from her own answers to an autobiographical questionnaire and narrated in the first person:

“...I start thinking about how good it’s going to feel to 

take that first hit...with my eyes wide open I take my 

lighter out of my pocket, put it to the stem, and get ready 

to take that first, good blast....”

The researchers injected each woman with a radiotracer 

and took pictures of the blood flow in her brain as she 

listened to the script and relived the scene in her mind. 

After each brain scan, the women rated the urge to use 

cocaine, vividness of the mental image, and their 

emotions. They repeated this process twice.

The women also underwent imaging in three control situations: resting, listening to a script of a personal experience in nature, and listening to a script designed to provoke anger. The researchers verified that the mental imagery of the cocaine-related script induced a greater urge to 

use cocaine than the nature or anger script. By comparing 

the brain scans produced in response to the different 

scripts, the researchers were able to evaluate 

cerebral blood flow while the women were craving cocaine 

versus when they were relaxed and not thinking of the 

drug. The procedure also distinguished changes related to 

Selected Key Brain Regions Affected by Cue-Induced 

Cocaine Craving in Cocaine-Addicted People 

(Cocaine-use imagery compared with neutral imagery)

Brain Region Putative Role in Behavior Activity Changes During Cocaine Craving

Men Women

Right nucleus 

accumbens

Processes anticipated and attained 

rewards—probably 

contributes to the expectation 

of pleasure during craving

Increased activity Increased activity

Amygdala

Generates and regulates emotional 

responses; assesses the positive or 

negative value of experiences and 

forms associations between experiences and emotional consequences

Increased activity Decreased activity

Dorsal 

anterior 

cingulate 

cortex

Monitors competing options, inhibits goal-inappropriate behavior, and 

plans movements related to obtaining rewards; activity 

influenced by past experiences—

possibly provides cognitive control 

of drug-seeking behavior 

Increased activity

Increased activity, 

greater than that 

of men

Ventral anterior 

cingulate 

cortex

Regulates emotional response 

to cocaine cues; activation may 

precede craving onset

Increased activity Increased activity, less 

than that of men

Frontal 

cortex

Monitors relationship of drug 

cue to drug availability; provides 

inhibition or control over actions; 

activity influenced by past 

experiences—possibly counterregulates emotional input

Increased activity

Increased activity, 

greater than that 

of men
66

craving from those that might simply reflect 

strong general emotional reactions (as in 

the anger-inducing script). To examine 

possible sex differences in the neural representation of cocaine craving, the investigators compared the findings in women 

with results from eight cocaine-addicted 

men of similar ages and backgrounds 

who experienced the same process.

In both men and women, cue-induced 

cocaine craving activated several brain 

areas involved in determining a cue’s 

reward value and controlling rewardrelated behaviors, including the right 

nucleus accumbens—a structure that 

seems to produce the expectation of 

pleasure during drug craving (see table, 

“Selected Key Brain Regions Affected 

by Cue-Induced Cocaine Craving in 

Cocaine-Addicted People”). “These common activations suggest that both sexes 

may process cocaine-use memories—

mental images that are associated with 

strong emotions—as cues that guide 

reward-based decisionmaking,” says Dr. 

Kilts. However, men and women also 

showed some dissimilar neural responses 

to cocaine cues. Most notably, activity of 

the amygdala—a structure that assesses 

whether an experience is pleasurable or 

aversive and connects the experience 

with its consequences—fell in women 

during cocaine craving. “This finding 

is notable because our study and others 

have shown cue-induced amygdala activation in men,” says Dr. Kilts. “Reduced 

neural responses in the amygdala may 

result from greater activation of the 

frontal cortex in women. The frontal 

cortex inhibits the activity of structures 

involved in emotional responding to 

drug cues, and our observations were consistent with previously reported sex differences in frontal cortical areas.”

“As a field, we need more and better controlled studies of 

sex differences in factors that cause relapse,” says Dr. Kilts. 

Combining imaging technologies in the same study—for 

example, PET with magnetoencephalography—would 

improve the localization of neural activity. “We could better define the neural responses that occur before, during, 

and after drug cues—illuminating the temporal sequence 

of the craving experience in men and women,” he says.

“This research reveals that men and women differ in a 

critical brain area in their responses to cocaine craving,” 

says Dr. Steven Grant of NIDA’s Division of Clinical 

Neuroscience, Development, and Behavioral Treatments. 

“Differences in the amygdala may indicate that male and 

female abusers crave the drug for different reasons or hope 

to achieve different results from taking the drug. Imaging 

studies that examine gender differences in specific behavioral aspects of drug craving will provide insight on how 

to tailor treatment programs to meet the needs of men 

and women.”

Source

• Kilts, C.D.; Gross, R.E.; Ely, T.D.; and Drexler, 

K.P.G. The neural correlates of cue-induced craving 

in cocaine-dependent women. American Journal of 

Psychiatry 161(2):223-241, 2004. 

Brain Response Differs in Men and Women 

During Cue-Induced Craving

These PET scans show differences in blood flow between a neutral state and a cocainecraving state. White areas indicate an increase in blood flow. Most notable is the decrease 

in blood flow in the women’s amygdala (top right panel) during craving; men show an

increase in blood flow during craving (bottom right panel).
Research Findings

67

Sigma Antagonists: Potential Cocaine Medications With 

Novel Activity

By Patrick Zickler, NIDA NOTES Staff Writer

Volume 19, Number 4 (December 2004)

Investigators in NIDA’s Intramural Research Program 

(IRP) have confirmed and extended previous findings 

that rimcazole, a medication developed in the 1980s to 

treat schizophrenia, weakens some of cocaine’s effects in 

rodents. The new findings strengthen speculation that 

drugs like rimcazole that act at sigma receptors might 

help recovering individuals avoid temptations to relapse 

to cocaine. Rimcazole and related compounds share a 

novel mechanism of action, a sigma receptor blockade, 

that appears to have significant potential for loosening 

cocaine’s hold on addicted individuals. 

Drs. Jonathan Katz and Amy Newman and IRP colleagues 

showed that pretreating mice with rimcazole reduced one 

of cocaine’s signature effects on rodent behavior: increases 

in locomotor activity—more running around. The impact 

on movement varied with the dosages of rimcazole and 

cocaine: At the maximum, a 73 μmol/kg dose of rimcazole 

reduced by 57% the amount of locomotor activity rats 

exhibited following administration of cocaine (40 mg/

kg). Other rimcazole-like compounds reduced locomotor 

activity following cocaine exposure by up to 47%, also 

depending on dosages.

The demonstration that rimcazole attenuates locomotor 

stimulation by cocaine confirms previous similar findings by other researchers. The IRP team established for 

the first time an additional potentially important effect of 

rimcazole-like compounds: In rats, a closely related compound called SH3-28 weakens the subjective sensations 

that distinguish the cocaine experience. Rats pretreated 

with SH3-28 lost some of their ability to tell the difference between injections of cocaine and injections of 

saline—plain salt water. 

In this experiment, the 

researchers first taught rats 

they could obtain food by 

choosing the correct lever 

between two options: To be 

rewarded, the animals needed to push one lever after 

receiving a cocaine injection 

and the other lever after 

receiving a saline injection. 

Once trained, rats pressed 

the cocaine-associated lever 

nearly 100% of the time 

after an injection of cocaine; 

however, when pretreated 

with 19 μmol/kg of SH3-28 

prior to receiving cocaine, 

they pushed the correct lever 

only about 60% of the time. 

Should these results carry 

over to people, rimcazole or 

a rimcazole-like medication 

might be used in treatment 

of cocaine abuse. Recovering 

individuals who abused 

cocaine while taking the 

medication would learn that 

the drug did not produce the 

Coadministration of 

Rimcazole With Cocaine 

Blocks Locomotor 

Stimulation in Mice

Pretreatment With Rimcazole 

Analog SH3-28 Decreases 

Subjective Effects of 

Cocaine in Rats

When administered with cocaine, rimcazole 

blocked the stimulant effects of cocaine on locomotor activity.

In rats conditioned to press a lever in response to 

cocaine injection, SH3-28 pretreatment reduced 

the accuracy of the animals’ responses to cocaine. 
68

desired stimulant sensations, reducing their motivation for 

future use.

“This area of research is still in the early stages of effectiveness testing, but if the present results prove reliable 

and can be extended to humans, it would appear that 

rimcazole and its analogs may have promise in further 

drug discovery efforts toward the treatment of cocaine 

abuse,” says Dr. Frank Vocci, director of NIDA’s Division 

of Pharmacotherapies and Medical Consequences of Drug 

Abuse.

The Mechanisms of Action

Rimcazole achieves its cocaine-suppressing effects at least 

in part by binding to and blocking the sigma receptor. 

This is a protein on the surface of some brain cells that 

receives chemical messages and relays them to the interior 

of the cells, stimulating or inhibiting some cellular activities. Compounds that block the sigma receptor inhibit 

cells from responding to dopamine, a chemical messenger 

that contributes to many of the addictive effects of cocaine 

as well as of other addictive drugs.

Rimcazole also binds to another protein on the cell surface, called the dopamine transporter. Most chemicals that 

attach here mimic the effects of cocaine, which itself is a 

potent dopamine transporter blocker. The IRP researchers 

are currently investigating whether rimcazole and 

rimcazole-like compounds produce an effect opposite to 

cocaine’s because their sigma blockade overrides their dopamine transporter effect, or whether some more complicated interaction between the two comes into play. So far, 

the evidence seems to point to the latter possibility.

“Our findings suggest that the interaction of sigma receptor ligands and cocaine is complex and appreciably different from competitive antagonism—that is, rimcazole and 

its analogs do not appear to physically block cocaine from 

its binding site,” says Dr. Katz. “It is possible that the 

effects of these compounds are due to the particular balance of dopamine transporter and sigma receptor actions 

they produce.” 

The IRP team’s research constitutes the initial studies in 

a program of drug discovery. Future investigations will 

examine whether rimcazole and related compounds block 

other stimulant-induced effects of cocaine, attempt to isolate the exact nature of their effects at the sigma receptor 

and dopamine transporter, and—if the compounds continue to show promise—evaluate their safety and efficacy 

in animals and people.

Source

• Katz, J.L., et al. Behavioral effects of rimcazole analogs alone and in combination with cocaine. European 

Journal of Pharmacology 468(2):109-119, 2003. 
Research Findings

69

Behavioral Modification Changes the Brain’s Biochemical Response 

to Cocaine, Curbs Relapse Caused by Stress

By Tom Hollon, NIDA NOTES Contributing Writer

Volume 19, Number 3 (September 2004)

The scientific view of drug addiction as a chronic brain 

disease rests on many studies showing that addictive drugs 

change the brain in ways that cause compulsive drug 

seeking and drug taking. NIDA research recently demonstrated that the converse can also sometimes be true: In 

rats, behavioral modification changed the biochemistry 

of the brain and thereby reduced the motivation to selfadminister cocaine.

Dr. David W. Self of the University of Texas 

Southwestern Medical Center in Dallas and colleagues 

at the Yale University School of Medicine and Harvard 

Medical School induced cocaine dependency in a set of 

experimental animals and then examined the impact of 

the behavioral technique called “extinction training” on 

the rats’ behavior and glutamate receptors in one of the 

brain’s major communications systems. Their finding that 

the training increased quantities of the glutamate receptors 

underscores the potential effectiveness of behavioral treatments for addiction and relapse prevention.

Extinction Training and Glutamate

The researchers began their experiments by training rats to 

self-administer cocaine at will by pressing a lever. Animals 

trained in this way become “cocaine dependent”—that 

is, they develop behavioral and neurobiological changes 

that simulate the effects of addiction in people. The rats 

then underwent extinction training. In this technique, the 

researchers put animals into cages where they have selfadministered a drug, but with a difference: Now, when 

the animals press the lever, no drug is dispensed. After a 

number of tries—more for some, less for others—the animals lose interest in the lever. Basically, extinction training reeducates animals, teaching them that the association 

between pressing the lever and getting a drug no longer 

holds.

In their first experiment, the researchers measured how 

extinction training affected the frequency of the cocainedependent rats’ lever pressing and the supply of two glutamate receptors in the part of the brain known as the shell 

of the nucleus accumbens (NAc). The receptors, GluR1 

and GluR2, act as relays in the brain’s glutamate system, 

which uses the neurotransmitter glutamate to send messages from cell to cell.

As expected, extinction training changed the rats’ behavior: Among the rats that received it, the frequency of 

lever pressing declined from a range of 39-44 presses in 

a 4-hour interval to a rate equivalent to 22-34 presses. 

These rats were also found to have 39% more GluR1 

and 31% more GluR2 than matched cocaine-dependent 

rats not subjected to extinction training. Strengthening 

the conclusion that extinction training was responsible 

for these increases, the sizes of the declines in lever pressing correlated with the amount of increase in GluR1. 

Rats whose declines exceeded the median averaged a 58% 

increase in GluR1, while those whose declines were less 

than the median averaged a 24% increase.

“We discovered something profound—that simply allowing an animal to press a lever and not get any drug completely changed the brain’s response to cocaine,” Dr. Self 

says.

A second experiment confirmed the relationship between 

the glutamate receptors and successful extinction training. It also showed that the relationship goes the other 

way, too: Having more receptors at the time of extinction 

training increases the response to the training. In preparaStronger Training Response Correlates 

With Higher Receptor Levels

Rats that responded more strongly to extinction training showed 

greater increases in glutamate receptor levels. Rats that did not 

receive training demonstrated a decrease in glutamate receptors. 

Percent changes shown are relative to control rats not exposed to 

cocaine.
70

tion for this experiment, the researchers used genetic engineering to artificially increase GluR1 and GluR2 in some 

cocaine-dependent rats’ NAcs. In the first hour of training, these animals pressed levers for cocaine roughly 20 

times, while animals whose receptors were not enhanced 

performed about 40 lever presses. The animals with the 

extra glutamate receptors also achieved the milestone of 

fewer than 20 lever presses after only 2 to 2.5 days of 

training, compared with more than 4 days for the other 

animals.

Summarizing the results of the two experiments, Dr. Self 

says, “There is a reciprocal relationship between extinction 

training and the level of glutamate receptors. Extinction 

training causes transient increases in glutamate receptors, while higher quantities of glutamate 

receptors facilitate extinction of drugseeking behavior.”

To explain why rats with enhanced glutamate receptors are more likely to pass 

up cocaine, Dr. Self points to one of the 

key functions of the glutamate system: It 

helps enable an animal or a person forego 

short-term pleasures for the sake of safety 

or longer-term goals. In this situation, 

the prefrontal cortex, the brain’s seat of 

foresight and planning, releases glutamate molecules into the NAc, the brain’s 

pleasure center, that override the motivation for the short-term pleasure. Previous 

research has shown that chronic cocaine exposure reduces 

the cortex’s glutamate production, weakening its influence 

over the pleasure center. Dr. Self suggests that increasing 

the number of glutamate receptors in the NAc may partially compensate for the glutamate shortage by relaying 

more signals from the glutamate that still remains.

A more difficult question—one the researchers are pursuing now—is why extinction training increased glutamate 

receptors in the NAc. Although cocaine also caused glutamate shortages in rats that were taken off it without 

extinction training, those animals did not respond with 

compensatory increases in receptors.

Stress and Relapse

In a subsequent experiment, Dr. Self and his colleagues 

demonstrated that raising GluR1 levels in the NAc 

reduced formerly dependent rats’ tendency to respond to 

stress by reverting to cocaine self-administration. Most 

surprising, the reduction in response was documented 3 

weeks after the elevated GluR1 levels returned to normal.

After inducing cocaine dependency, genetically increasing 

the supply of glutamate receptors in the NAc, and a single 

session of extinction training, the researchers gave their 

experimental rats a 3-week timeout. Then, they returned 

the rats to their training cages and administered three 

types of stimulus: a “priming” dose of cocaine, a light 

that flashes when the lever in the cage is ready to dispense 

cocaine, and a series of mild electrical shocks to the paw. 

These stimuli correspond to triggers that commonly cause 

addicted people to relapse—drug exposure, environmental 

cues associated with previous drug use, and stress. Each 

usually causes rats to revert to drug self-administration. 

Dr. Self and his colleagues found, however, that when 

their extinction-trained rats received foot shocks, those 

whose GluR1 levels were higher resumed lever pressing 

about 87% less frequently than those with less GluR1.

“This was really surprising,” says Dr. Self. “It suggested 

that glutamate receptor increases during extinction training have long-term effects on stress-induced relapse, even 

after receptor quantities return to normal.”

To account for this finding, Dr. Self suggests that “there is a similarity between 

stress and extinction training. Foot shock 

is mild and basically irritates the animal, 

the rat equivalent of a bad day at work. 

Extinction is stressful too—the frustration of looking for a drug you anticipate 

but don’t get. Perhaps extinction training 

teaches the animal to cope with stress by 

inhibiting craving, which stress normally 

would increase.”

Dr. Nancy S. Pilotte of NIDA’s Division 

of Neuroscience and Behavioral Research 

agrees that behavioral changes sustained 

beyond the transient period of glutamate 

receptor elevation are an important finding. “This tells 

you it is extremely important to follow animals after drugs 

are withdrawn, a stage of addiction we know fairly little 

about,” she says. “We know a lot about acute affects, but 

very little about what happens to animals when they are 

no longer receiving drugs.”

Currently, no equivalent to extinction training exists 

for treating people. However, Dr. Self believes that in 

the future, virtual reality technology may make such an 

approach possible. “A very realistic video game might 

make it possible to recreate many of the anticipatory and 

emotional responses involved in preparing for the drug 

experience without ever actually receiving the drug,” he 

explains. “Repeated ‘virtual drug taking’ could extinguish 

these emotional responses by strengthening the brain 

pathways that exert inhibitory behavioral control over 

drug craving.”

Source

• Sutton, M.A.; Schmidt, E.F.; Choi, K-H.; Schad, 

C.A.; Whisler, K.; Simmons, D.; Karanian, D.A.; 

Monteggia, L.M.; Neve, R.L.; and Self, D.W. 

Extinction-induced upregulation in AMPA receptors 

reduces cocaine-seeking behaviour. Nature

421(6918):70-75, 2003. 

“Perhaps extinction 

training teaches the 

animal to cope with 

stress by inhibiting 

craving, which stress 

normally would 

increase.”
Research Findings

71

Brain Glutamate Concentrations Affect Cocaine Seeking 

By Tom Hollon, NIDA NOTES Contributing Writer

Volume 19, Number 3 (September 2004)

NIDA-supported research has produced evidence that a 

medication that supplements recovering cocaine addicts’ 

brain concentrations of the neurotransmitter glutamate 

may reduce their vulnerability to relapse. Although the 

research was done with laboratory rats, the substance used 

to bolster glutamate levels was acetylcysteine, a medication 

that is safe for humans and used routinely in emergency 

rooms to treat overdoses of the analgesic acetaminophen.

Dr. Peter Kalivas and colleagues at the Medical University 

of South Carolina in Charleston measured the glutamate 

concentrations in the fluid surrounding the cells in rats’ 

nucleus accumbens (NAc) in the absence of cocaine exposure; after training the animals to voluntarily self-administer the drug by pressing a lever in their cage; and 3 weeks 

after removing the animals’ access to cocaine. Compared 

with the concentrations in nonexposed animals, those during cocaine self-administration were markedly higher, and 

those after forced abstinence markedly lower. The investigators concluded that rats repeatedly exposed to cocaine 

develop glutamate concentration deficits in the NAc that 

persist for a considerable time after access to the drug is 

removed. 

Dr. Kalivas and colleagues next investigated whether 

cocaine or acetylcysteine would restore the rats’ glutamate 

levels and the effect on the animals’ motivation to selfadminister cocaine. As in their first trials, the researchers 

began by training rats to press a lever to obtain cocaine, 

then removed the cocaine from the solution the rats 

received when they pressed the lever. As before, these 

procedures left the rats with reduced NAc glutamate 

concentrations; the rats also lost interest in pressing the 

lever because it no longer delivered cocaine. At this point 

the researchers injected some of the animals with a single 

dose of cocaine and others with a dose of acetylcysteine 

followed by a dose of cocaine. The initial cocaine and acetylcysteine doses both increased glutamate to the elevated 

levels that followed cocaine self-administration. However, 

the rats given only cocaine resumed drug-seeking behavior—they began pressing the lever to try to self-administer 

cocaine—while those given acetylcysteine prior to cocaine 

did not.

“Restoration of glutamate by acetylcysteine blocked reinstatement of drug seeking in rats trained to self-administer 

cocaine,” Dr. Kalivas says. “This strongly indicates that 

susceptibility to relapse is due in part to diminished levels 

of extracellular glutamate associated with drug withdrawal. 

Our finding could well apply to people, too, since selfadministration and reinstatement in animals are reliable 

models of addiction and relapse in humans.” 

Dr. Kalivas’ findings add to a growing body of information describing glutamate’s important role in the neurobiological processes underlying drug abuse and addiction. 

Glutamate is a neurotransmitter, a chemical that acts as a 

messenger between brain cells. NIDA investigators have 

lately focused attention on glutamate in part because it 

influences levels of another neurotransmitter, dopamine, 

in the brain’s pleasure center, the NAc. Fluctuations in 

NAc dopamine levels underlie the euphoria of initial drug 

use and contribute to other aspects of cocaine and other 

drug abuse and addiction. Glutamate signals also amplify 

the addictive effects of nicotine (see “Nicotine’s Multiple 

Effects on the Brain’s Reward System Drive Addiction,” 

NIDA NOTES, Vol. 17, No. 6, p. 1), and contribute to 

a condition called “long-term potentiation,” which causes 

brain cells that have been exposed to addictive drugs to 

release dopamine more abundantly in response to subsequent exposure (see “Addictive Drugs and Stress Trigger 

Similar Change in Brain Cells, Animal Study Finds,” 

NIDA NOTES, Vol. 18, No. 5, p. 1).

A Possible Addiction Therapy, 

Built From the Ground Up

Training chambers like this one are used to study animals’ 

responses to drugs. By pressing the lever, the rat obtains an infusion of a drug, a medication, or saline through the tube. Using 

such apparatus, NIDA scientists showed that cocaine abuse reduces brain glutamate levels, and treating animals with acetylcysteine 

reduces subsequent cocaine seeking.
72

The scientists’ successful use of acetylcysteine to restore 

normal glutamate levels supports their hypothesis that 

cocaine reduces glutamate concentrations in the fluid surrounding cells in the NAc. They suspect that repeated 

drug exposure followed by drug withdrawal disrupts a 

process known as cystine-glutamate exchange: molecules 

of cystine enter NAc nerve cells, which pump molecules of 

glutamate out in exchange. The exchange normally maintains appropriate concentrations of both chemicals inside 

and outside the cells, but disruption by drugs may result 

in a shortage of extracellular glutamate. The researchers 

speculate that acetylcysteine rectifies this shortage because 

it forms cystine molecules when it is metabolized. These 

molecules then enter the cells and prompt them to pump 

out additional glutamate.

Dr. Nancy S. Pilotte of NIDA’s Division of Neuroscience 

and Behavioral Research says Dr. Kalivas’s glutamate 

research demonstrates the value of moving beyond studies 

that focus on the dopamine-triggered pleasure associated 

with abuse and addiction. “We need to move on from 

thinking of dopamine as the center of the universe,” she 

says, adding that the payoff for broader research perspectives may be “more molecular targets for development of 

medications.”

Following up on the results of his animal studies, Dr. 

Kalivas has begun a clinical trial to determine whether 

acetylcysteine can control substance abuse patients’ craving for cocaine once they have achieved abstinence. He 

and his colleagues are also conducting further laboratory 

studies to evaluate whether the compound may prevent 

animals from seeking opioids or alcohol as effectively as it 

prevents them from seeking cocaine. 

Source

• Baker, D.A.; McFarland, K.; Lake, R.W.; Shen, H.; 

Tang, X.C.; Toda, S.; and Kalivas, P.W. 

Neuroadaptations in cystine-glutamate exchange 

underlie cocaine relapse. Nature Neuroscience

6(7):743-749, 2003. 
Research Findings

73

Cocaine Abusers’ Cognitive Deficits Compromise Treatment 

Outcomes

By Arnold Mann, NIDA NOTES Contributing Writer

Volume 19, Number 1 (April 2004)

Cognitive impairment may be an important factor in 

explaining treatment failure among cocaine abusers, according to results from a new NIDA-funded study by Dr. Efrat 

Aharonovich and colleagues at New York’s Columbia 

University. These findings are already leading researchers to 

modify current treatments for cognitively impaired cocaine 

abusers, with hopes of improving success rates.

Cognitive-behavioral therapy (CBT) is an effective treatment for cocaine addiction, but dropout rates range from 

33 to 64 percent. This study is the first to examine the role 

of impaired cognition as a contributor to this statistic. The 

researchers found that patients with impaired attention, 

learning, memory, reaction time, and cognitive flexibility—

all documented consequences of chronic cocaine abuse—

were much more likely to drop out of the 12-week CBT 

program than those not cognitively impaired. In addition, 

the dropout rate was related to the degree of cognitive 

impairment, with the more impaired patients more likely to 

stop treatment.

“These data show very clearly that cocaine abusers with 

cognitive deficits are most likely to drop out of [CBT] treatment,” says Dr. Aharonovich. This is particularly true during the first 4 weeks of treatment, when the dropout rate 

is highest. Further, she adds, cognitively impaired patients 

who manage to stick it out beyond the first 4-week course 

are “most likely not going to do as well” as patients without 

cognitive deficits.

The impetus for the study, Dr. Aharonovich notes, was realizing that “some patients were coming to sessions and just 

not ‘getting it.’ We were losing a lot of patients. I thought 

maybe we were delivering a treatment that they were receiving but not understanding.”

In CBT’s one-on-one therapy sessions, the therapist teaches 

the patient to recognize the connections between the 

thoughts, feelings, and actions that undermine his or her 

attempts to become abstinent. Patients are taught to avoid 

specific situations associated with their drug abuse, to use 

techniques like “thought stopping” to cope with cravings, 

and to focus on emotions that may trigger drug use.

“You have to be pretty intact cognitively to really stick with 

CBT,” says Dr. Edward Nunes, a researcher in the study. 

“This is a therapy that involves a lot of analyzing, thinking 

ahead, planning, and controlling impulses. If the cognitive 

functioning is a little off, it’s going to make it hard for those 

patients to thrive in treatment.”

Cocaine abusers’ cognitive deficits have been well documented. The drug constricts cerebral blood vessels, resulting 

in decreased blood flow to the brain. Magnetic resonance 

imaging (MRI) studies also reveal an increased presence of 

microvascular lesions and clots in cerebral blood vessels, 

which can also restrict blood flow. Chronic cocaine use can 

also deplete the neurotransmitter dopamine, which contributes to impaired cognition. 

Eighteen cocaine-addicted patients participated in the study. 

All tested positive for cocaine use in the previous 72 hours 

and reported using cocaine at least four times in the month 

before admission and for at least 12 months before study 

enrollment. Patients were excluded from the study if they 

were HIV-positive or had conditions known to cause cognitive impairment independently of cocaine abuse, including 

mood disorders, psychosis, attention-deficit/hyperactivity 

disorder, seizure disorders, or a previously diagnosed learning 

disability.

Each patient was scheduled for 15 once-a-week, 1-hour 

CBT sessions. Eleven patients received gabapentin, a medication used to quell cravings; the remaining seven received a 

placebo. Urine specimens were collected three times a week 

and analyzed for cocaine and six other commonly abused 

drugs. Patients who attended at least 12 CBT sessions were 

Cognitive Status a Factor in Cocaine 

Abusers’ Time in CBT*

Cognitively impaired cocaine abusers are more likely than abusers 

with higher cognition to drop out of outpatient CBT, particularly 

in the first 4 to 6 weeks.
74

considered completers, based on the standard 12-week CBT 

treatment.

When the researchers analyzed the data, there were no 

significant differences in age, sex, ethnicity, employment, 

or education between treatment dropouts and completers. 

Prior duration of cocaine use 

was similar for both quitters and 

completers. Of the 11 patients on 

medication, 7 dropped out; 5 of 

the 7 patients on placebo dropped 

out. Thus, the overall completion 

rate for all patients in the study 

was 33 percent. Medication had 

no effect on the study results, the 

researchers concluded.

Big differences emerged, however, in the cognitive abilities of dropouts and completers. 

The researchers used MicroCog computerized testing to 

determine each patient’s level of cognitive performance at 

admission. Treatment completers performed at higher cognitive levels than dropouts across all the measured cognitive 

domains—attention, abstract reasoning, memory, spatial 

processing, and reaction time. Completers also performed 

significantly faster and with greater accuracy on proficiency 

testing than did dropouts, and they required significantly 

less time to complete cognitive tasks than the dropouts.

Patients in the low-cognition group were more likely to 

drop out early, during the first 4 weeks of treatment, than 

those in the high cognition group—55 percent versus 22 

percent. And the average proportion of drug-free urine 

specimens among patients in the high-cognition group was 

significantly higher than in the low-cognition group. 

“The dropout rate was higher for patients with more 

impairment and lower for the patients with less impairment,” says Dr. Nunes.

“We finally have empirical data to very clearly show that 

patients with cognitive impairments at treatment entry are 

more likely to drop out of CBT,” says Dr. Aharonovich. “If 

you are able to process what the therapist is telling you, you 

are more likely to stay in treatment. But if you can’t, you’re 

more likely to drop out.”

One potential response, Dr. Aharonovich suggests, is to 

prescreen patients and provide modified treatment for the 

cognitively impaired—a smaller curriculum, or “CBT Lite,” 

as she puts it. The goal would be to simplify tasks and pare 

down the number of topics and skills covered, much as a 

teacher would do with learning-disabled children. “In the 

fragile first 4 to 6 weeks of treatment,” she says, “I would, 

for example, propose increasing session frequency from 

60 minutes once a week to 30 minutes twice a week. This 

would decrease session lengths and reduce the demands on 

memory and attention.” 

To augment this strategy, greater use of visual techniques, 

like node-link mapping, is recommended. “This is a modification of CBT,” says Dr. Nunes. “Instead of just talking 

about the sequence of events that leads up to use—the 

places, people, thoughts, cravings—the therapist diagrams it 

all out.”

Cognitive remediation techniques, or 

“brain exercises,” which recently showed 

positive results in a study by Dr. William 

Fals-Stewart, may help the cognitively 

impaired patient, observes Dr. Nunes, as 

may drug therapies designed to improve 

cognitive ability. At Yale University in 

New Haven, Connecticut, for example, 

Dr. Thomas Kosten has begun trials 

using amiloride to improve cerebral 

blood flow in patients addicted to 

cocaine. Drs. Aharonovich and Nunes 

and Dr. Adam Bisaga, also at Columbia, 

are now testing memantine, which has been used in Europe 

to prevent brain cell damage in Alzheimer’s patients and 

patients suffering from other forms of dementia. 

The problem with medications, Dr. Aharonovich says, is 

getting enough cognition restored quickly to combat the 

high dropout rate in the first 4 weeks of therapy. “Usually, 

these medications require more than 4 weeks to take effect,” 

she says, “so we need to do something to modify the therapy at the very beginning to be able to capture patients and 

hold them in treatment.”

“Dr. Aharonovich’s research supports the notion that a 

substantial number of drug abusers have some degree of 

cognitive impairment that could impede their ability to get 

the most benefit from treatment,” says Debbie Grossman, 

M.A., of NIDA’s Division of Treatment Research and 

Development. “This study highlights the importance of 

considering the cognitive functioning of drug abuse patients 

so that cognitive remediation can be incorporated into 

treatment, and/or treatments can be adapted and matched 

to the cognitive ability of the patient. Further research is 

critically needed to develop, modify, and test ‘cognitivefriendly’ drug dependence treatments that could lead to 

improved treatment response and outcome.”

Sources

• Aharonovich, E., et al. “Cognitive impairment, 

retention and abstinence among cocaine abusers in 

cognitive-behavioral treatment.” Drug and Alcohol 

Dependence 71(2):207-211, 2003.

• Grohman, K., and Fals-Stewart, W. Computerassisted cognitive rehabilitation with substance-abusing 

patients: Effects on treatment response. Journal of 

Cognitive Rehabilitation 21(4):2-9, 2003.

• Kosten, T.R., et al. “Aspirin or amiloride for cerebral 

perfusion defects in cocaine dependence.” Drug and 

Alcohol Dependence 71(2):187-194, 2003. 

“If you are able to process 

what the therapist is telling 

you, you are more likely to 

stay in treatment. But if you 

can’t, you’re more likely to 

drop out.”
Research Findings

75

Volume 18, Number 6 (February 2004)

At the culmination of a research journey that began more 

than 20 years ago, GVG (vigabatrin)—a medication widely 

used to treat epilepsy outside the United States—is about 

to be tested in large-scale clinical trials that will determine 

whether its promising pharmacological properties can 

translate into effective treatment medication for cocaine 

abuse. Winning FDA approval of any pharmaceutical therapy for use in the United States is an exacting, costly, timeconsuming process. It involves lengthy research, testing in 

animals and, finally, testing in increasingly larger groups of 

selected, medically suitable humans to show that the drug 

is not only therapeutically effective, but safe to use. Testing 

medications to treat drug addiction is especially challenging, as it involves recruiting—and gaining the support and 

cooperation of—drug-addicted people.

After more than 20 years, it appears that GVG is nearing 

the final hurdles to winning FDA approval for use in treating cocaine addiction. Detailed below is this long journey, 

not untypical of the process many medications go through 

before providing relief to their intended recipients.

Identifying GVG’s Promise

In the 1980s, Dr. Stephen L. Dewey of Brookhaven 

National Laboratory in Upton, New York, and a colleague, Dr. Jonathan D. Brodie of the New York University 

School of Medicine in New York City, were seeking new 

treatments for schizophrenia. “Very few people in the mid1980s looked at interactions between neurotransmitter systems, but rather examined transmitter systems independently,” explains Dr. Dewey. As studies continued over years 

and preliminary research showed that GVG modulates 

GABA, which in turn reduces dopamine levels, the scientists launched a long series of preclinical experiments testing 

GVG’s potential as a treatment medication for addiction.

“Two decades and 15 publications later, we knew that 

GVG can safely block the biochemical effects of addictive 

drugs—nicotine, morphine, methamphetamine, amphetamine, ecstasy, and alcohol—including the increased brain 

dopamine levels they trigger,” Dr. Dewey says. “This

medication can also block the behavioral fallout from 

dopamine surges: drug self-administration, changes in 

brain-stimulation reward threshold, relapse resulting from 

addiction-induced cues, and drug sensitization—the 

Developing a medication to treat cocaine addiction has 

long been a research priority of NIDA’s Medications 

Development Program. According to the National 

Survey on Drug Use and Health, an estimated 2 million people were current cocaine users in 2002. The 

available treatment offerings for these individuals as 

well as people addicted to methamphetamine and other 

stimulant drugs are exclusively behavioral, as no treatment medications have yet proven effective.

Dr. Frank Vocci, Director 

Division of Treatment Research and Development

The Long Road to Medication Development: 

Cocaine Treatment Moves to Clinical Trials

By Neil Swan, NIDA NOTES Contributing Writer 

Cocaine increases dopamine levels in animals to as much as 500

percent of normal levels in critical brain areas. However, when 

animals are given GVG before being given cocaine, their dopamine 

levels increase to no more than twice normal levels, indicating the 

reward-reinforcement response has been blocked or greatly reduced.

GVG Blocks Cocaine-Triggered 

Dopamine Increases in Animals
76

need to consume more and more of a drug to achieve 

dopamine-based feelings of pleasure.”

With evidence of GVG’s ability to block the addictive 

effects of all psychostimulants, the researchers focused 

their research on its potential as a pharmaceutical therapy 

for cocaine addiction. Throughout this research, Dr. 

Dewey charted how dramatically GVG therapy inhibits 

cocaine-induced increases in brain dopamine levels in 

animals. However, plans to test GVG as a treatment for 

cocaine abuse in humans were sidetracked in 1998, when 

research showed that 10 to 30 percent of epilepsy patients 

taking the drug lost some portion of their normal field of 

vision.

Meeting a Safety Challenge

Not willing to give up on GVG’s potential, Dr. Dewey 

and his Brookhaven colleagues set out to find a lowdosage course of GVG that could 

effectively block the addictive 

responses of cocaine in rats without impairing their vision. The 

researchers’ strategy: compare the 

effects of a single large dose of 

150-450 mg/kg GVG with those 

of the same total dose administered over 3 days, at 50-150 mg/

kg per day. The scientists found 

that the anti-addictive effect of 

GVG persists when it is administered gradually. The drug inhibited the effect of cocaine after a 

3-day “washout” period when 

GVG administration stopped. 

Further, the inhibitory effect of 

gradual administration actually 

exceeded in magnitude and duration the effect of the identical 

total one-shot dose, 

the researchers found.

The researchers concluded that 

people can probably sustain GVG 

maintenance therapy, possibly for 

years, with little or no increased 

risk of developing medicationinduced vision defects.

Launching Clinical Trials

Using human dosages based on 

the GVG dosages that safely 

countered cocaine’s effect in 

rats and primates, Drs. Dewey 

and Brodie launched a clinical 

trial with 20 cocaine abusers in 

a drug treatment center directed 

by Dr. Emilia Figueroa in Mexicali, Mexico. Following 

the dosing strategy devised for animals, the researchers 

introduced GVG therapy with a strategy of “ramping the 

patients’ doses up, and then tapering them off,” explains 

Dr. Dewey.

Of the 20 patients enrolled in the study, 8 remained in 

the program and were drug-free for periods of 46 to 58 

days. Twelve enrollees failed to complete the clinical trial; 

of these, 8 dropped out within the first 10 days, having 

decided they were not ready to stop abusing cocaine. Four 

enrollees participated in the study for 25 to 43 days while 

continuing to abuse cocaine, albeit in greatly reduced 

amounts. Most patients who completed the trial reported 

losing their craving for cocaine after 2 to 3 weeks of GVG. 

Once they stopped cocaine abuse, 6 of the 8 completers 

 Of 20 cocaine abusers enrolled in a GVG clinical trial, 8 completed the trial (28-day abstinence plus 21-day taper) and were drug-free for 46 to 58 days total. Once cocaine use ceased, 6

of the 8 completers were entirely drug-free for the duration of the study. Most patients who completed the trial reported that their craving for cocaine stopped 2 to 3 weeks after receiving GVG.

Cocaine Users Achieve Abstinence,

Remain Drug-Free With GVG
77

were drug-free for the duration 

of the study. No vision problems 

were reported.

Encouraged by the Mexico 

results, the researchers look forward to the next step—a larger, 

double-blind, placebo-controlled 

trial that they hope to initiate soon in Toronto, Canada. 

Catalyst Pharmaceutical Partners, 

which holds the license from 

Brookhaven to develop GVG as a 

treatment for drug addiction, has 

helped move this trial forward. 

Another smaller trial is also being projected for the United 

States. Dr. Frank Vocci, Director of NIDA’s Division of 

Treatment Research and Development, says that NIDA 

is ready to cooperate once FDA gives its approval to go 

ahead. 

“We are still early in the clinical trial process,” notes Dr. 

Vocci. “However, if additional trials safely and successfully 

replicate early treatment results, GVG has the potential 

to provide us with an effective medication for preventing 

relapse in cocaine-dependent patients.”

Commenting on the impressive GVG research record, Dr. 

Vocci concludes, “The data these 

researchers have compiled is the 

most comprehensive on a potential medication for addiction 

therapy that we’ve seen,” he says. 

“It’s a very interesting medication that involves a very interesting mechanism.”

Sources

• Brodie, J.D.; Figueroa, E.; and Dewey, S.L. Treating 

cocaine addiction: From pre-clinical to clinical trial 

experience with �-vinyl GABA. Synapse 50(3):261-

265, 2003.

• Schiffer, W.K.; Marsteller, D.; and Dewey, S.L.

Sub-chronic low dose �-vinyl GABA (vigabatrin) 

inhibits cocaine-induced increase in nucleus accumbens dopamine. Psychopharmacology 168(3):339-343, 

2003. 

If additional trials safely and 

successfully replicate early 

treatment results, GVG has 

the potential to provide us 

with an effective medication for preventing relapse in 

cocaine-dependent patients.
Research Findings

78

Cocaine May Compromise Immune System, Increase Risk of 

Infection

By Patrick Zickler, NIDA NOTES Staff Writer

Volume 18, Number 6 (February 2004)

Cocaine abusers are more likely than nonusers to suffer 

from HIV, hepatitis, sexually transmitted diseases, and 

other infections. Most of this increased incidence is the 

result of conditions and behaviors—for example, injecting drugs, poor nutrition, and unsafe sex—that often are 

associated with drug abuse. Now, NIDA-supported investigators at the McLean Hospital Alcohol and Drug Abuse 

Research Center in Belmont, Massachusetts, have found 

that cocaine itself has a direct biological effect that may 

decrease an abuser’s ability to fight off infections. 

Dr. John H. Halpern, along with colleagues at McLean 

Hospital and Harvard Medical School, found that a key 

immune system component, a protein called interleukin-6 

(IL-6), responded less robustly to an immunological challenge in male and female abusers injected with cocaine than 

in those who received placebo. “When your body detects a 

foreign object, IL-6 helps trigger the release of a cascade of 

other immune system components that isolate and neutralize the threat,” explains Dr. Halpern. “If the balance of this 

response is disrupted, your body cannot fight infection as 

effectively as it should.”

The study involved 30 participants (16 women, 14 men, 

ages 21-35) with a history of cocaine abuse, including at 

least one drug administration within the past month. The 

investigators placed an intravenous catheter in one arm of 

each participant and measured IL-6 levels. The catheter is 

detected as foreign by the body’s immune system and triggers an immune response. After 30 minutes, the researchers 

injected cocaine or saline solution (0.4 mg/kg) into each 

participant’s other arm; 4 hours later, they measured IL-6 

levels again. In participants given saline, IL-6 levels had 

more than quintupled in response to the presence of the 

catheter, increasing from an average of less than 

2 trillionths of a gram (picograms, or pg) per milliliter of 

blood to an average of more than 11 pg/ml. In men and 

women who received cocaine, however, IL-6 levels barely 

doubled—from less than 2 pg/ml to an average of 3.8 pg/

ml. 

“The findings in this study show that in people with a 

history of cocaine abuse, exposure to the drug establishes 

conditions that can lead to immediate harm,” Dr. Halpern 

says. “In such subjects, we found that cocaine impairs the 

body’s defense system for at least 4 hours. We can’t rule 

out the possibility that IL-6 response returns to normal 

shortly after that time. But even if the blunted immune 

response lasts only a few hours, it makes it more likely 

that an infection like HIV or just a common cold can take 

hold,” Dr. Halpern says.

“This research suggests a link between cocaine use and 

compromised immune response and could help explain 

the high incidence of infectious disease among drug abusers,” observes Dr. Steven Grant of NIDA’s Division of 

Treatment Research and Development. “It reminds us that 

the health consequences of drug abuse reach far beyond 

disruption of the brain systems involved in abuse and 

addiction.” 

The findings also have significance in another context, Dr. 

Grant adds. “The IL-6 findings are a small but possibly 

significant part of a much larger study designed to gather 

a wide range of information on the acute and chronic 

effects of abused drugs on the brain, endocrine system, and 

immune function. This kind of discovery-based research 

can yield unexpected, sometimes important, insights.”

Source

• Halpern, J.H., et al. Diminished interleukin-6 response 

to proinflammatory challenge in men and women after 

intravenous cocaine administration. Journal of Clinical

Endocrinology and Metabolism 88(3):1188-1193, 2003. 

Elevations in the protein interleukin-6 (IL-6) play a key role in

resisting infections when viruses, bacteria, or foreign objects, such as 

a catheter, enter the body. IL-6 elevations following insertion of a

catheter were smaller in volunteers given cocaine than in volunteers 

given saline, suggesting that the drug may impair cocaine users’ 

ability to fight off infectious diseases.

Cocaine Use May Increase Infection Risk
79

Research Findings

Volume 18, Number 1 (June, 2003)

New Animal Model Simulates Human Exposure, Confirms Harm 

From Prenatal Cocaine

By Kimberly Martin, NIDA NOTES Contributing Writer 

Research has shown that some children exposed in the 

womb to cocaine may have memory and attention deficits 

that hinder their ability to learn. These children also may 

have difficulties completing complex tasks or tests that 

involve distractions, and they tend to perform poorly on 

visual recognition memory and attention tasks.

Now, Dr. Bret Morrow and his colleagues at Yale 

University have demonstrated in rats that prenatal exposure to cocaine may cause long-term changes in an area 

of the brain responsible for short-term memory. Previous 

animal studies have reported negative effects of cocaine 

on cognitive performance, but doubts persisted about the 

applicability of study results to humans. The new findings 

help allay those doubts, which are based partly on differences in how people use cocaine and in how cocaine was 

administered to rats in earlier experiments. By designing 

an experiment that closely simulates the way humans use 

cocaine, the Yale team has enhanced the applicability of 

cognitive impairment in rats prenatally exposed to cocaine 

to that observed in children.

“To more closely replicate the way human fetuses are 

exposed to cocaine, we administered the drug to the 

pregnant rats intravenously. This enabled us to use dosages 

similar to those taken by people. Also, the way cocaine is 

absorbed and metabolized when it is administered 

intravenously is much closer to what we see in humans,” 

says Dr. Morrow. “Additionally, tests commonly used in 

rat studies to assess cognitive deficits—maze and swimming 

tests—rely on artificial manipulation of the animal’s 

environment, such as food restriction, reward, or stress. 

Our test, a two-object recognition task that relied on the 

rat’s own motivation to complete the task, is comparable to 

one used with human infants to assess short-term memory.”

Cocaine was administered to pregnant rats twice a day 

for 11 days before they gave birth. At ages equivalent to 

human adolescence and adulthood, the male offspring 

were placed in a cage with two identical objects, allowed 

to explore the objects, then removed from the cage. After 

delays of 20 minutes, 1 hour, and 24 hours, the rats were 

returned to the cage with one of the former objects and 

a new object. The time a rat spent actively exploring the 

new and former objects was recorded. If he spent more 

time exploring the new object, the rat was considered to 

remember the former object. To count as “exploring” 

time, the rat had to be actively exploring the object, with 

his nose within about 2 cm of the object.

“The rats that were not exposed to cocaine spent more 

time exploring the novel object than the familiar object 

after 20-minute and 1-hour delays, but not after 24 

hours,” says Dr. Morrow. “We interpreted this behavior 

as memory of the familiar object from the previous 

exposure. The rats that were prenatally exposed to cocaine 

did not demonstrate a preference for the novel object over 

the familiar object at any time. This behavior was interpreted as their having no memory of the familiar object. 

These findings indicate that in the rat model, prenatal 

exposure to cocaine may result in long-lasting deficits in 

short-term memory.”

In a separate study, the researchers found that adolescent 

rats prenatally exposed to cocaine as described above had 

long-term changes in the frontal cortex. They showed 

excess activation of neurons in the prefrontal cortex, the 

brain area governing short-term memory. Activation was 

measured by the concentration of Fos, a protein produced 

by excited neurons. “Fos activation during development 

can change the way a neuron responds in the future; in 

other words, it undergoes a long-term adaptation,” says 

This rat is exploring an object during the two-object recognition 

task. He was previously exposed to one object, whereas the other is 

new. The rat was considered to remember the former object 

if he spent more time exploring the new one. Rats exposed to 

cocaine before birth did not demonstrate a preference for the 

new object, indicating no memory of the familiar object.

Two-Object Recognition Test 

Mimics Test Used with Infants

Photo credit: Dorothy Cameron, the Johns Hopkins University Bloomberg School of Public Health.
80

Dr. Morrow. “In some cases, this may indicate important 

adaptations that help the animal meet new challenges. 

However, in cocaine-exposed animals, we believe that the 

excessive Fos activation may lead to deficits in attention 

and memory.”

“This type of animal model is valuable in guiding research 

into the possible mechanisms and consequences of 

exposure to drugs of abuse during human development,” says Dr. Laurence Stanford of NIDA’s Division of 

Treatment Research and Development. “Animal models 

allow us to reduce the number of variables and confounding factors that are present when pregnant women abuse 

drugs. Research with children strongly suggests a significant dose effect, with the severity and presence of deficits 

linked to the extent of exposure. Maternal health may 

also play a role in the effects of prenatal drug exposure. 

For example, the appetite-suppressing effects of cocaine 

and resulting nutritional deficits can contribute to growth 

retardation in the womb. For the purposes of reducing the 

number of variables, and thus attempting to isolate the 

effects of prenatal cocaine exposure, this research is a 

valuable experiment.”

“This animal model may prove valuable not only for 

probing neurological and cognitive deficits caused by 

prenatal cocaine exposure, but also for testing potential 

therapies,” says Dr. Susan Volman of NIDA’s Division 

of Neuroscience and Behavioral Research.

Sources

• Morrow, B.A., et al. Prenatal cocaine exposure disrupts nonspatial, short-term memory in adolescent 

and adult male rats. Behavioral Brain Research 129

(1-2):217–223, 2002.

• Morrow, B.A., et al. Male rats exposed to cocaine in 

utero demonstrate elevated expression of Fos in the 

prefrontal cortex in response to environment. 

Neuropsychopharmacology 26(3):275–285, 2002. 
81

Research Findings

Joint Treatment of PTSD and Cocaine Abuse May Reduce 

Severity of Both Disorders

By Robert Mathias, NIDA NOTES Staff Writer 

Many individuals who abuse cocaine, alcohol, and other 

substances also suffer from posttraumatic stress disorder 

(PTSD) related to life-threatening or other traumatic 

events they have experienced or witnessed. Individuals 

with PTSD suffer recurring flashbacks, anxiety, and other 

symptoms that can impede substance abuse treatment. 

Similarly, substance abuse can make PTSD symptoms 

worse. Thus, integrated treatment is recommended as 

the way to treat patients with both disorders. Yet until 

recently, the most effective nonpharmacological treatment 

for PTSD, known as exposure therapy, was considered too 

risky to use with cocaine-dependent patients. The therapy 

seeks to desensitize patients to the distressing emotional 

effects of the trauma that triggered their PTSD by requiring them to repeatedly and graphically describe it.

“Researchers and clinicians have been reluctant to use 

exposure therapy with cocaine-dependent patients,” 

says Dr. Kathleen Brady of the Medical University of 

South Carolina in Charleston. “Drug abuse patients were 

thought to be likely to turn to alcohol and drugs to cope 

with the emotional demands placed on them by recounting the fear-inducing experience.”

A preliminary study led by Dr. Brady suggests that the 

belief that exposure therapy would do these patients more 

harm than good may not be merited. In the study, instead 

of triggering emotional distress and relapse to substance 

abuse, treatment that combined exposure therapy for 

PTSD with substance abuse counseling produced substantial improvement in both disorders.

Thirty-nine cocaine-dependent individuals with PTSD, 

32 of them women, participated in the outpatient study. 

The majority of participants had developed PTSD following such severe traumatic experiences as rape (74 percent), 

aggravated assault (89 percent), and other physical assault 

(95 percent). Individuals who feel intense fear and helplessness or horror during such terrifying events can later 

develop distressing symptoms that can impair their ability 

to live and work normally.

PTSD symptoms fall into three general categories: “intrusions,” such as flashbacks or nightmares in which the 

person reexperiences the traumatic event; “hyperarousal” 

or anxiety, which can be marked by extreme vigilance and 

jumpiness, difficulty sleeping or concentrating, and irritability; and “avoidance” of people, activities, and situations 

that might trigger memories of the incident. When symptoms persist for more than 3 months, PTSD is considered 

chronic. Chronic sufferers often have additional psychiatric disorders. An estimated 30 to 60 percent of individuals 

with substance abuse disorders have PTSD, according to 

studies cited by Dr. Brady.

Combination Psychotherapy Reduces 

Posttraumatic Stress Disorder (PTSD) 

Symptoms and Cocaine Use

Fifteen cocaine-dependent patients with PTSD who completed a 

psychotherapy that addressed both disorders significantly reduced 

cocaine use and had fewer and less intense PTSD symptoms, as 

assessed by physicians.

Volume 18, Number 1 (June, 2003)
82

The study used a psychotherapy developed by Dr. Brady 

and her colleagues that combines counseling for drug 

abuse with exposure therapy for PTSD. “We wanted to 

evaluate whether cocaine-dependent PTSD patients could 

safely tolerate the therapy and whether it would be effective in reducing the severity of their PTSD symptoms 

and cocaine use,” Dr. Brady says. The combined therapy 

consists of 16 90-minute individual sessions. In the first 

3 weeks, patients participate in two counseling sessions a 

week that concentrate solely on their drug abuse problems 

and developing relapse prevention skills. “The therapy 

in those first sessions gives people a chance to experience 

some sobriety and provides them the coping techniques 

and strategies they will need to deal with high-risk situations and the urges to use drugs they may experience 

when they get into the exposure therapy,” Dr. Brady says.

Once patients start to feel comfortable sharing their feelings with the therapist and are willing to engage in exposure therapy, a technique called imaginal exposure is used 

to address their PTSD symptoms. In imaginal sessions, 

patients describe in detail the circumstances and feelings 

they experienced during the traumatic event that triggered their disorder. They also develop a list of situations 

or places they have been avoiding because they associate 

them with the event. Between sessions, patients carry out 

assignments in which they gradually expose themselves 

to similar situations that are safe but fear-inducing. If, 

for example, they were abducted from a parking lot and 

assaulted, they may have become fearful of any parking 

lot or areas with cars in them. Assignments could involve 

going to such areas, first with a friend, then by themselves 

in the middle of the day. 

“We are trying to get at the irrational fears and inappropriate avoidance of situations that are interfering with 

their lives,” Dr. Brady says. “By talking about their experience over and over in the imaginal sessions, they are basically reliving it. The point of the exposure is to desensitize 

them to the trauma, thereby reducing the fear, anxiety, 

and emotion from the memory itself. By the end of successful therapy, patients are able to go through their entire 

traumatic scenario and feel much less distressed because 

they are able to separate irrational fears from simply thinking about the event.”

The goal of the therapy is that the intrusion, arousal, and 

avoidance symptoms all recede. The exposure has done 

its job when someone can go through his or her detailed 

recalling of the event and score no higher than 5 on a 

20-point scale that measures how much distress they are 

feeling, says Dr. Brady. 

Fifteen of the 39 study participants completed the combined therapy, attending at least 10 of the 16 sessions, 

including a minimum of 3 exposure therapy sessions. 

Assessments by both patients and clinicians indicated that 

those who completed treatment experienced significant 

reductions in all three PTSD symptom categories and in 

cocaine use from study entry to treatment completion.

Using a self-administered Impact of Events Scale, patients 

reported a 53-percent reduction in “intrusion” symptoms and a 27-percent reduction in inappropriate avoidance behaviors. Over the same period, clinicians using a 

30-item structured clinical interview tallied a 66-percent 

reduction in “intrusions,” a 70-percent reduction in 

“avoidances,” and a 47-percent reduction in hyperarousal 

symptoms. By the end of treatment, completers also had 

reduced cocaine use by 60 percent and reported experiencing significantly fewer substance-related problems. 

Followup assessments indicated that treatment completers 

had maintained these improvements in both PTSD symptoms and cocaine use 6 months after treatment ended. 

In contrast, no differences emerged in any PTSD or 

substance-abuse-related scores at treatment completion 

or 6 months later among noncompleters. 

“This study provides promising preliminary evidence 

that exposure therapy can be used safely and effectively 

in treating PTSD in some cocaine-dependent individuals 

without increasing the risk of relapse,” says Dr. Brady. 

The improvements in PTSD symptoms were comparable 

to those reported by other studies that used exposure 

therapies to treat patients with no substance abuse disorder. Dropout rates, though high, also were similar to those 

in previous studies that used other psychotherapies to treat 

cocaine-dependent patients.

Nevertheless, the small number of patients in the study 

and the high dropout rates underscore the need for randomized controlled studies to replicate these results, Dr. 

Brady cautions. Such studies also could provide information that would help to identify patients who are likely to 

benefit from this treatment, as well as those who might 

need different approaches.

Source

• Brady, K.T., et al. Exposure therapy in the treatment 

of PTSD among cocaine-dependent individuals: 

Preliminary findings. Journal of Substance Abuse 

Treatment 21(1):47–54, 2001.
Research Findings

83

Researchers Probe for Clues to ADHD Medications’ 

Protective Effects

By Jill Schlabig Williams, NIDA NOTES Contributing Writer, and Patrick Zickler, NIDA NOTES Staff Writer 

More than 2 million American children—an estimated 

5 to 10 percent of preteens—have been diagnosed with 

attention-deficit/hyperactivity disorder (ADHD). For many 

of these children, treatment with psychostimulant medications such as Ritalin (methylphenidate, or MPH) suppresses 

the impulsivity, fidgeting, and inability to concentrate 

that characterize the disorder. Appropriate use of psychostimulants in children with ADHD also has been shown 

to reduce the likelihood that these children will develop 

drug or alcohol use disorders when they reach adolescence 

and adulthood. (see “Studies Link Stimulant Treatment of 

ADHD in Childhood to Lower Risk of Later Substance 

Abuse” on page 43).

While the benefits of psychostimulant treatment for 

ADHD are clear, scientists are only beginning to explore 

how these medications help protect children with ADHD 

against later drug abuse. Two possible explanations have 

been proposed—one neurobiological and the other 

psychosocial. Stimulant medications might make drugs 

less desirable through direct neurobiological effects in the 

brain that reduce the pleasurable effect that drugs elicit. 

A second explanation is that the medications may reduce 

children’s vulnerability by helping them act less impulsively, 

perform better in school, and relate better to others, thereby 

reducing negative feelings and the likelihood of joining 

socially deviant peer groups—psychosocial characteristics 

known to be risks for drug-taking. Possibly, both 

mechanisms contribute to reduced risk.

Two recent NIDA-supported studies have begun to 

investigate the neurobiological effect of stimulant medications by studying rats exposed to MPH. Researchers at 

the McLean Hospital in Belmont, Massachusetts, and the 

Chicago Medical School exposed rats to MPH during 

periods when the animal brain is in developmental stages 

that correspond to human childhood and adolescence.

Scientists stipulate that while responses observed in laboratory 

animals are suggestive, they do not necessarily indicate 

that humans will be affected in the same way. Moreover, 

because researchers have yet to identify the specific brain 

features that give rise to ADHD, it is even less possible to 

say whether the current results with MPH have relevance 

for young people who receive MPH for that disorder. 

With those caveats, however, the results of these preliminary studies suggest that MPH does have a neurobiological effect that lasts into adulthood. 

Exposure During Childhood

At McLean Hospital, Dr. Susan Andersen and her colleagues injected groups of eight male rats with either MPH (2 

mg/kg) or saline twice daily. The animals were exposed to 

the medication during a period when the rat brain is in a 

developmental stage equivalent to human childhood—on 

days 20 through 35 following birth. At adulthood (day 60), 

the rats were tested with a method called place conditioning, 

in which they learn to associate drug effects with a particular 

environment. On two consecutive days, the rats received

Volume 18, Number 1 (June, 2003)

Adult Rats Exposed to MPH (Ritalin) 

During “Childhood” Spent Less Time in 

Cocaine-Associated Environment

Before place conditioning, rats spent equal time in the saline- and 

cocaine-associated rooms. After place conditioning, rats exposed to saline 

in childhood showed a dose-related preference for the cocaine-associated 

room. However, MPH-exposed rats actively avoided the room they 

had been conditioned to associate with cocaine at a 10 mg/kg dose. 

Although these rats spent slightly more time in the room they associated 

with cocaine at a 20 mg/kg dose, this difference did not reach the level 

of statistical significance and thus did not show that they were attracted 

to this room more than the saline-associated room.
84

two conditioning trials in which both saline-exposed and 

MPH-exposed rats were given saline and confined for 

1 hour to a side room of a three-room cage before being 

returned to the central room. Three hours later, the rats 

received cocaine in a 5, 10, or 20 mg/kg dose and were 

confined to the other side room for 1 hour before being 

returned to the central room. On the third day of the 

study, the rats were allowed to freely explore the entire 

cage for 30 minutes, while researchers measured the time 

they spent in the room associated with saline and in the 

room associated with cocaine.

Adult rats that initially received placebo in childhood 

showed a dose-related preference for the room associated with cocaine. The higher the dose of cocaine they 

received, the more time they spent in the room they had 

learned to associate with cocaine. However, the MPHexposed rats did not follow this pattern. After receiving 

either moderate or high cocaine doses, they did not 

establish place preference for the cocaine-associated room. 

MPH-exposed rats that received a moderate cocaine dose 

tended to avoid the cocaine-associated room, spending less 

time there than in the saline-associated room. MPH rats 

that received a high dose of cocaine spent slightly more 

time in the cocaine-associated room, but only about onethird as much time as the unexposed rats. “Their response 

was definitely blunted,” Dr. Andersen says.

The findings reported by Dr. Andersen’s research group 

suggest that, in rats, MPH exposure has a neurobiological effect that is protective later in life. “Rats exposed to 

MPH during the period equivalent to human childhood 

experience behavioral changes that endure into adulthood 

and are more sensitive to cocaine’s unpleasant effects,” 

Dr. Andersen observes.

Despite these findings, Dr. Andersen cautions, it is still 

too early to make assumptions about any neurobiological 

effect of MPH on vulnerability to cocaine abuse.

“There is still a great deal of research to be done in this 

area. We need to investigate the role of dose, gender, age 

of exposure, and treatment duration and to examine how 

MPH affects other reward systems, such as responses to 

sex or food,” concludes Dr. Andersen. 

Exposure During Adolescence

At the Chicago Medical School, Dr. Cindy Brandon, Dr. 

Frank White, and colleagues exposed male rats to daily 

doses of MPH (2 mg/kg) or saline from days 35 to 42 

after birth, when the rats are going through a period of 

brain development corresponding to human adolescence. 

When the rats reached adulthood (56 days of age), they 

were put into boxes with two holes into which they could 

poke their noses. Poking through one hole triggered an 

infusion of cocaine (75 �g/kg). Poking through the other 

hole triggered an infusion of saline solution. The scientists 

recorded the number of pokes in both holes over 5 days. 

Rats that had not been exposed to MPH during adolescence 

triggered few infusions, and the rate did not increase over 

the course of the experiment. Rats that had been exposed 

to MPH in adolescence, however, began self-administering 

cocaine on the first day and triggered increasingly more 

infusions on each successive day. By day 5, they were selfadministering cocaine at a rate more than seven times that 

of the rats not exposed to MPH. “Adult animals exposed 

to MPH during adolescence were considerably more 

vulnerable to the reinforcing effects of cocaine,” Dr. White 

explains. “From these results, it is reasonable to suspect 

that in humans, adolescent exposure to MPH may increase 

future vulnerability to low doses of cocaine.”

Implications for Future Research

This study, like the work done by Dr. Andersen’s group, 

suggests that exposure to MPH has a neurobiological 

effect that persists into adult life. However, in this study, 

the effect is to increase risk rather than to confer protection. 

“It’s important to keep in mind that my study and Dr. 

Adult Rats Exposed to MPH 

(Ritalin) During “Adolescence” 

 Self-Administered More Cocaine 

Adult rats exposed to MPH during the period corresponding to 

human adolescence self-administered significantly more cocaine 

than did rats exposed to placebo in adolescence. Rats self-administered 75 �g/kg of cocaine by poking their noses into a hole in their 

treatment chamber. This action switched on an infusion pump for 

3 seconds, delivering cocaine via a jugular catheter.
85

Andersen’s study measured two different behaviors. Place 

preference studies can be seen as a model of the 

animals ‘wanting’ the drug, while self-administration 

studies involve actually taking the drug. These methods 

are not measuring the same processes in the brain,” 

Dr. Brandon says.

“What these animal studies suggest is that, on a neurobiological level, early exposure to MPH has effects that 

persist into later life,” says Dr. Susan Volman of NIDA’s 

Division of Neuroscience and Behavioral Research. “They 

also indicate that the timing of exposure—whether the 

animals are exposed during childhood or adolescence—

plays a role in later behavior in the animals.”

Only continued investigation will clarify the extent to 

which the neurobiological results seen in rats, which do 

not have ADHD, might also be relevant to humans with 

or without ADHD. “There’s still a great deal we need to 

learn about exposing a developing brain to MPH,” Dr. 

Volman says. “We just don’t know enough yet about the 

enduring changes that may result.”

Sources

• Andersen, S.L., et al. Altered responsiveness to 

cocaine in rats exposed to methylphenidate during 

development. Nature Neuroscience (5)1:13–14, 2002.

• Brandon, C.L.; Marinelli, M.; Baker, L.; and White, 

F.J. Enhanced reactivity and vulnerability to cocaine 

following methylphenidate treatment in adolescent 

rats. Neuropsychopharmacology 25(5):651–661, 

2001. 

Children treated for attention-deficit/hyperactivity 

disorder (ADHD) with stimulant medications are 

less likely to develop substance abuse disorders 

later in life than are children with ADHD who are 

not given stimulants, according to NIDA-supported 

researchers. Dr. Timothy Wilens and his colleagues 

at the Massachusetts General Hospital and Harvard 

Medical School in Boston reviewed long-term studies in which stimulant-treated and untreated children 

with ADHD were evaluated later in life and concluded that stimulant therapy cuts in half the likelihood 

of subsequent substance abuse disorders.

The researchers examined six studies with a combined total of 647 children with ADHD who had 

been treated with stimulants and 360 who had not. 

On average, the studies followed up on the participants for 6 years (range 4 to 15 years) after treatment ended and they were more than 20 years old 

(range 15 to 22 years of age). Four of the six studies included treated and untreated participants with 

similar severity in their initial diagnoses. The studies found less incidence of any substance abuse 

disorder in participants treated with stimulants. One 

study in which the severity of initial diagnosis was 

not similar for treated and untreated groups found 

that participants who received stimulants were more 

likely to smoke and to abuse cocaine, but not more 

likely to abuse alcohol or marijuana. The other study 

in which diagnostic severity was not matched found 

that stimulant-treated participants were more likely 

to abuse alcohol or marijuana.

“Considering all six studies, there was an almost 

twofold decrease in the likelihood of substance 

abuse disorders risk for youths treated previously 

with stimulant medication,” Dr. Wilens says.

The Harvard group’s findings counter concerns 

voiced by some practitioners that exposure to stimulants might increase children’s disposition to subsequently abuse drugs. “These findings should reassure clinicians and families by providing compelling 

evidence that pharmacotherapy with stimulants for 

ADHD does not lead to substance abuse disorders, 

but instead seems to have protective effects,” says 

Dr. Wilens.

Source

•	 Wilens, T.E., et al. Does stimulant therapy of

attention-deficit/hyperactivity disorder beget later 

substance abuse? A meta-analytic review of the 

literature. Pediatrics 111(1):179–185, 2003. 

Studies Link Stimulant Treatment of ADHD in Childhood to Lower Risk 

of Later Substance Abuse
Research Findings

86

Cocaine’s Effect on Blood Components May Be Linked to 

Heart Attack and Stroke

By Patrick Zickler, NIDA NOTES Staff Writer 

Cocaine use increases the risk of sudden heart attack and 

may also trigger stroke, even in users who otherwise are 

not at high risk for these sometimes fatal cardiovascular 

events. The risk is related to narrowing of blood vessels 

and increases in blood pressure and heart rate. Recently, 

NIDA-supported researchers at the Alcohol and Drug 

Abuse Research Center at McLean Hospital in Belmont, 

Massachusetts, have identified changes in blood components that may also play a role in cocaine-related heart 

attack and stroke.

Dr. Arthur Siegel and his colleagues studied the effect of 

cocaine on blood factors that respond to inflammation by 

promoting clotting to initiate repair. They found that a 

component that promotes clotting—von Willebrand factor 

(vWF)—increases and remains elevated for hours after a 

single exposure to cocaine. They also found that, compared 

with less frequent users, heavy users of cocaine have elevated 

levels of vWF, fibrinogen (a clotting factor), and C-reactive 

protein (CRP), a blood protein that increases in concentration in response to inflammation and is a reliable indicator 

of risk for heart attack.

“These findings suggest that cocaine creates a temporary 

risk for heart attack or stroke by increasing clotting factors,” Dr. Siegel explains. “Elevated CRP levels could 

indicate that long-term use of the drug is triggering 

inflammation in the cardiovascular system.”

Participants in the study were 20 individuals (10 women 

and 10 men, average age 26 years) who used cocaine 2 

to 6 times per month but were drug free at the time of 

the study. They received injections of low (0.2 mg/kg) or 

moderate (0.4 mg/kg) doses of cocaine or of saline solution, 

and their clotting-related blood components were measured 

every 30 minutes for 4 hours. In participants who received 

moderate doses of cocaine, but not those receiving lowdose cocaine or saline, levels of vWF increased by roughly 

40 percent and remained elevated for 4 hours.

“With healthy subjects, it’s not unusual to see a temporary 

increase in vWF after normal activity such as exercise,” 

Dr. Siegel says. “But the increase is balanced by higher 

levels of factors that control clotting. The increases that 

followed cocaine administration were not accompanied by 

compensatory increases in protective factors.”

The researchers also compared the blood factor levels 

of the original study participants to those of 10 other 

individuals (6 women, 4 men, average age 41 years) who 

used the drug far more heavily—6 to 20 times per week, 

on average—when both groups were drug free. The heavy 

cocaine users had higher levels of vWF, fibrinogen, 

and CRP.

“Elevated levels of CRP and clotting factors that we see in 

the heavy users suggest that repeated use of cocaine poses 

an exposure-related and cumulative risk for heart attack or 

stroke,” Dr. Siegel says. “The fact that neither group showed 

any compensatory increase in anticlotting mechanisms 

Volume 17, Number 6 (March, 2003)

Cocaine users who reported heavy use (6 to 20 times per week)

show higher levels of C-reactive protein, von Willebrand factor,

and fibrinogen—blood components that contribute to clotting—

than do less frequent users (2 to 6 times per month).

Key Blood Component Levels Are 

Higher in Heavy Cocaine Users
87

suggests that cocaine use upsets the body’s ability to maintain 

a balance between risk and protective factors and tips the 

scale toward increased risk for heart attack or stroke.”

The findings are preliminary, Dr. Siegel cautions, and based 

on a relatively small sample of cocaine users. “Other factors certainly play a role in CRP levels, and cocaine alone is 

probably not responsible for the elevated levels we found. 

For example, age is a factor but does not account for all of 

the difference. Smoking also may be a factor. In our study, 

cocaine users who smoked had higher CRP levels than 

those who did not. On the whole, these findings suggest 

that cocaine compounds the effects of other risk factors.”

If larger studies confirm the relationship between elevated 

CRP levels and cumulative cocaine exposure, the blood 

component may serve as a marker for damage, Dr. Siegel 

says. Moreover, he adds, “measuring CRP is simple and 

inexpensive, and could be used as a test for the effects 

of cocaine in much the same way as blood composition 

is used to test for diabetes. It could serve as an objective 

measure of risk for heart attack and stroke and provide a 

way for patients and treatment providers to assess progress 

during drug treatment.”

Sources

• Siegel, A.J., et al. Cocaine-induced erythrocytosis and 

increase in von Willebrand factor. Archives of Internal 

Medicine 159:1925–1930, 1999. 

• Siegel, A.J., et al. Effect of cocaine usage on 

C-reactive protein, von Willebrand factor, and fibrinogen. American Journal of Cardiology 89:1133–1135, 

2002. 
Research Findings

88

Study Finds Significant Mental Deficits in Toddlers Exposed to 

Cocaine Before Birth

By Robert Mathias, NIDA NOTES Staff Writer 

Since the mid–1980s, up to 1 million children born in the United States are estimated to have been exposed to cocaine 

in the womb. Determining cocaine’s impact on these children’s development has been difficult because there often 

are other possible explanations for physical and mental 

problems the children may have, such as the mother’s use 

of other substances during pregnancy and poor prenatal 

care. Now, a NIDA-supported study that was able to 

separate the effects of cocaine from those of many other 

such factors has found that children born to poor, urban 

women who used cocaine throughout pregnancy were 

nearly twice as likely as children with similar backgrounds 

but no prenatal cocaine exposure to have significant cognitive deficits during their first 2 years of life.

The study, led by Dr. Lynn Singer of Case Western 

Reserve University in Cleveland, Ohio, is the first to show 

a clear association between prenatal cocaine exposure and 

cognitive impairment in 2-year-olds. “Since cognitive 

performance at this age is indicative of later performance, 

these children may continue to have learning difficulties 

that need to be addressed when they reach school age,”

Dr. Singer says. 

“The findings of this well-controlled study make an 

important contribution to a growing body of knowledge about the effects of prenatal cocaine exposure that 

may help us to identify those exposed children who are 

at increased risk of developmental harm,” says Dr. Vince 

Smeriglio of NIDA’s Center on AIDS and Other Medical 

Consequences of Drug Abuse. Previous findings from other 

NIDA-supported studies that have been following cocaineexposed children from birth have produced conflicting 

results about cocaine’s impact on developmental outcomes 

at this age, he notes. “Comparing and contrasting the 

circumstances in this study with those found in other 

studies of cocaine-exposed children may enable us to identify 

specific biological and environmental factors that increase 

or reduce the developmental risk from cocaine exposure,” 

Dr. Smeriglio says.

The study followed a group of 415 infants born at a large 

urban teaching hospital from 1994 through 1996 to 

mothers from low socio-economic backgrounds who had 

been identified by the hospital staff as being at high risk 

of drug abuse. Women who participated in the study were 

given urine tests for drug use immediately before or after 

delivery and interviewed shortly after they gave birth to 

produce estimates of the type, frequency, and amounts of 

drugs they had used during pregnancy. Each baby’s first 

stool, known as meconium, also was analyzed for the presence of cocaine and its metabolites to help establish the 

level of drug exposure. Of the 415 babies in the study, 

218 had been exposed to cocaine and 197 had not. Both 

groups of infants also had been exposed to tobacco, alcohol, and marijuana during pregnancy.

Researchers measured the children’s developmental progress at 6.5, 12, and 24 months of age with the Bayley 

Volume 17, Number 5 (January, 2003)

Tests of mental development at 6.5, 12, and 24 months

showed average scores of cocaine-exposed and unexposed 

children from comparable backgrounds were below the 

normative score of 100 for children in the general population. At age 2, cocaine-exposed children did significantly 

poorer in mental development than children in the comparison group.
89

Scales of Infant Mental and Motor Development. Motor 

tests assessed the infants’ ability to control and coordinate 

their movements. Mental tests assessed language, memory, 

and ability to solve problems at 12 and 24 months. For 

example, children were asked to describe objects in pictures, 

remember where an object had been hidden, and put shaped 

objects into the correct spaces cut out on form boards.

To isolate cocaine’s effect, researchers adjusted test results 

for the effect of other risk factors, such as other drugs used 

during pregnancy; characteristics of biological mothers 

and alternative caregivers; the infants’ head size, weight, 

length, and gestational age at birth; and the quality of 

their postnatal home environments. The analysis showed 

that while prenatal cocaine exposure had not affected 

the infants’ motor development, it was clearly linked to 

significant deficits in their cognitive performance at age 

2. Cocaine-exposed children scored 6 points lower on 

the Mental Development Index (MDI), averaging 82.7 

percent compared to 88.7 percent for unexposed children 

and an average general population score of 100. Other 

findings include the following:

• From 6.5 to 24 months, MDI scores declined for 

both groups, but cocaine-exposed children had a 

greater decline—14 points compared to a 9-point 

decline for unexposed children.

• Almost 14 percent (13.7 percent) of cocaine-exposed 

children had scores in the mental retardation range, 

below 70 on the MDI, nearly twice the 7.1-percent 

rate found in the unexposed children and almost five 

times the rate (about 2.8 percent) expected in the 

general population.

• Nearly 38 percent (37.8 percent) of cocaine-exposed 

children had developmental delays requiring remedial 

intervention, nearly double the 20.9 percent rate for 

unexposed children. 

The study found that other influences, including the 

mother’s intelligence scores and educational level, exposure to other substances, and the quality of the postnatal 

home environment, also played significant roles in poor 

outcomes for cocaine-exposed children. “However, after 

controlling for these factors in our analysis, we found that 

cocaine still has a harmful effect on cognitive performance,” 

Dr. Singer says. Additional support for this conclusion 

comes from mothers’ self-reports and biological data from 

mothers and infants that established a direct link between 

cocaine dose and toddlers’ cognitive performance. These 

data showed that children of mothers who used more 

cocaine and used it more frequently during pregnancy 

performed worse on the MDI than children of mothers 

who used less of the drug.

“The only risk factor we couldn’t completely control for 

is the effect of other drugs used during pregnancy,” Dr. 

Singer says, “because it is nearly impossible to find children 

who have been exposed only to cocaine.” The study partially 

adjusted for this influence by including children who had 

been heavily exposed to alcohol, tobacco, and marijuana 

in both groups. “Animal studies suggest there are possible 

synergistic effects of these drugs in combination, and the 

study may not have been large enough to control for these 

effects,” she notes. 

“We believe that cocaine exposure is a neurologic risk 

factor that may take a poor child who has a lower IQ 

potential because of maternal and other risk factors and 

push him or her over the edge to mental retardation,” 

Dr. Singer says. For example, average IQ scores for both 

cocaine-exposed and unexposed toddlers in the study were 

well below the average score for the general population. 

“In effect, cocaine lowered the range of IQ scores and that 

means more children may require early stimulation and 

educational programs,” she says.

“While many children in this study may require special 

educational services when they enter school, it is important 

not to assume that the findings from a single study, with 

its unique characteristics, necessarily apply to all cocaineexposed children,” cautions NIDA’s Dr. Smeriglio. 

Ultimately, NIDA’s extensive portfolio of research on 

groups of cocaine-exposed children being raised in a variety of settings should provide detailed information about 

mother, child, environment, and drug-use characteristics 

that can be used to develop interventions that reduce risk 

of harm and guide clinical care for cocaine-exposed children.

Source

• Singer, L.T., et al. Cognitive and motor outcomes of 

cocaine-exposed infants. JAMA 287(15):1952–1960, 

2002. 
Research Findings

90

Social Environment Appears Linked to Biological Changes in 

Dopamine System, May Influence Vulnerability to Cocaine Addiction

By Kimberly R. Martin, NIDA NOTES Contributing Writer 

Volume 17, Number 5 (January, 2003)

Cocaine is known to be a highly addictive drug; however, 

little is known about the factors that make some individuals more vulnerable to it than others. Recently, NIDAsupported researchers at Wake Forest School of Medicine 

in Winston-Salem, North Carolina, have provided potential insight as to why some drug abusers have an increased 

susceptibility to cocaine addiction. They have found a link 

in monkeys between environmental conditions, the brain 

chemical dopamine, and the addictive qualities of cocaine. 

In the study, transferring the animals from individual to 

social housing produced biological changes in some animals that decreased their response to cocaine.

Previous studies have indicated that certain environmental 

conditions—such as living in an enriched environment 

with access to more resources or reduced stress—may 

reduce animals’ self-administration of drugs, particularly 

cocaine. Animal studies also have suggested that environmental conditions may affect the activity of dopamine. 

Specifically, these studies have indicated that animals’ 

housing conditions and social rank can affect dopamine’s 

ability to bind to dopamine D2

 receptors and thereby 

initiate the cellular processes that produce feelings of pleasure and reward. Taken together, these findings inspired 

the Wake Forest researchers to look for a three-way link 

between environment, dopamine D2

 receptor function, 

and drug self-administration.

The researchers studied 20 macaque monkeys that were 

first housed individually and then assigned to social 

groups of 4 monkeys per housing group. Social hierarchies 

were allowed to develop in each group, and social rank 

was determined by observations of aggressive and submissive behavior. “Placement of the monkeys in social groups 

is modeling two extremes—socially derived stress for the 

most subordinate monkeys and environmental enrichment 

for the dominant monkeys,” said Dr. Michael Nader, who 

led the study. “Although these variables have been studied 

in other animal models, in our model the stressors and 

environmental variables were not artificially produced in 

the lab. The model also allows us to study issues related 

to cocaine-induced changes in social behavior and the 

interactions of those changes with the reinforcing effects 

of cocaine.”

Positron emission tomography (PET) was used to measure the amount and availability of dopamine D2

 receptors while the monkeys were individually housed and 3 

months after their placement into social groups. After the 

second PET scan, monkeys were trained to self-administer 

cocaine by pressing a lever. They were allowed access to 

cocaine during daily sessions; the rate of cocaine selfadministration was determined by the number of times 

the lever was pressed.

The second PET scan revealed that the monkeys that had 

become dominant now had 20 percent more dopamine 

receptor function compared to when they were housed 

alone. In the subordinate monkeys, dopamine receptor 

function was unchanged. Although dominant monkeys 

did not avoid cocaine completely, they had significantly 

lower intakes of cocaine than subordinate monkeys.

“The increase in markers of dopamine D2

 receptor function among dominant monkeys may be the result of 

an increase in the number of dopamine D2

 receptors, a 

decrease in the amount of circulating dopamine 

competing for the receptors, or both as a consequence 

In these PET scans, lighter colors represent increases in markers 

of dopamine D2 function. Greater levels of D2 markers in socially 

housed, dominant monkeys—attributed to their living in an 

enriched environment—suggest that positive changes in one’s environment can result in a biological protection from cocaine addiction.

Brain Images of Monkeys Housed Individually 

and After Transfer to Social Housing 
91

of becoming dominant,” says Dr. Nader. “This suggests 

that, regardless of an individual’s past, positive changes 

in the environment may result in a biological protection 

from the effects of cocaine. In other words, living in an 

enriched environment may enhance dopamine function 

and thus cause the pleasurable effects associated with 

cocaine use to be diminished.”

The Wake Forest team’s findings in monkeys have implications for understanding and possibly reducing drug 

abuse vulnerability in people. In people as in monkeys, 

drugs’ effects on dopamine levels and function are a key to 

the motivation for abuse. There is evidence that individuals with low levels of dopamine D2

 receptors have higher 

risk for abusing drugs. In these individuals, reduced 

dopamine function may produce less bountiful feelings 

of pleasure and reward from natural activities, making 

drug-induced euphoria more compelling. The new results 

suggest that it may be possible to identify environmental 

improvements that enhance individuals’ dopamine D2

receptor function and thereby lower their risk for drug 

abuse.

“Dr. Nader’s research shows that environmental experiences can increase dopamine D2

 receptor levels, which 

in turn are associated with a decreased vulnerability to cocaine self-administration,” says Dr. Cora Lee 

Wetherington of NIDA’s Division of Neuroscience and 

Behavioral Research. “This work, along with previous 

research regarding the role of dopamine D2

 receptors in 

drug abuse, points to the need for additional research to 

identify both environmental factors that promote low 

dopamine D2

 receptor levels and the associated vulnerability 

to cocaine’s reinforcing effects as well as environmental 

factors that give rise to high levels of dopamine D2

 receptors that confer resistance to cocaine’s reinforcing effects. 

Such research could point to risk and protective factors 

that could be translated into better prevention and treatment interventions.”

Source

• Morgan, D., et al. Social dominance in monkeys: 

Dopamine D2

 receptors and cocaine self-administration. Nature Neuroscience 5(2):169–174, 2002. 
Research Findings

92

Study Opens Promising New Approach to Developing Medications 

To Prevent Relapse to Cocaine Use

By Robert Mathias, NIDA NOTES Staff Writer

Cocaine treatment patients who encounter people, situations, or settings they associate with past drug abuse often experiVolume 17, Number 3 (October, 2002)

ence strong urges to use cocaine and slip 

back into addictive use. Such cue-induced 

relapse can occur long after patients have 

stopped using the drug. Now, research 

teams from Vrije Universiteit (VU) 

Medical Center in The Netherlands and 

NIDA’s Intramural Research Program 

(IRP) in Baltimore have shown that they 

can dramatically reduce cue-induced 

relapse to cocaine-seeking in rats by blocking 

a specific type of brain receptor that is activated by cannabinoids, a class of chemicals 

that includes the active ingredient in marijuana. The study opens a promising new 

approach to developing medications that 

may help to prevent cue-induced relapse 

to cocaine abuse by humans. 

“We found that blocking cannabinoid 

(CB-1) receptors in the brain reduces the 

relapse-provoking effects of stimuli associated with past cocaine use without interfering with the brain’s primary reward pathways,” says Dr. 

Taco De Vries, who led the experiments in Amsterdam. 

This finding suggests that medications similar to the 

compound (SR141716) the researchers used to block this 

receptor may be able to help cocaine treatment patients 

remain abstinent without diminishing their capacity to 

experience pleasure from normally rewarding activities, he 

notes. 

In the experiment, Dr. De Vries and Dr. Yavin Shaham 

of NIDA’s IRP first trained rats to self-administer cocaine 

by poking their noses into a specific hole in their chambers. During daily training sessions, a light was turned on 

to indicate when cocaine was available and an electrical 

switch was clicked while cocaine was being administered. 

Once rats responded regularly for cocaine, researchers 

turned off the cocaine supply for 2 weeks. As a result, 

when the rats poked their noses into the active hole during 

their daily drug-taking sessions, they got no cocaine and 

their drug-seeking behavior was gradually extinguished. 

The light and the clicking (light/click) cues that previously 

had accompanied cocaine administration were not turned 

on during these extinction sessions. 

The researchers then established that the rats would 

resume nose-poking at the cocaine-paired hole when they 

were exposed to any of three major stimuli known to provoke relapse to cocaine abuse by humans after periods of 

abstinence: 

• the drug itself—a computer-controlled injection of a 

priming dose of cocaine;

• drug-related environmental cues—the light/click 

stimuli previously linked to cocaine reward; and 

• stress—precipitated by intermittent electrical foot 

shocks. 

Administering a compound that blocked the rats’ CB-1 

receptors before exposure to these stimuli significantly 

reduced cocaine-seeking triggered either by the priming 

dose of cocaine or by reexposure to the light/click cues. 

The CB-1 antagonist did not affect resumption of cocaineseeking triggered by the footshock stressor. These results 

show that pharmacologically blocking the CB-1 receptor 

can selectively reduce the drug-stimulus effects of two of 

the three most common triggers of relapse to drug use.

Significantly, the researchers found that the CB-1 antagonist did not reduce cocaine self-administration in another 

SR141716, a compound that blocks rats’ CB-1 receptors, dramatically reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of 

relapse in humans: a priming dose of cocaine and environmental cues associated with 

cocaine reward. The compound did not reduce cocaine-seeking triggered by stress.

Compound Blocks Major Triggers of Drug Relapse
93

group of rats that had not had the drug withdrawn to 

extinguish their cocaine-seeking behavior. This result 

shows the compound did not alter the rats’ ability to experience cocaine’s primary rewarding effects, Dr. De Vries 

says. The CB-1 antagonist also did not deter rats from 

continuing to self-administer sucrose, another rewarding 

substance. Together, these experiments indicate that primary brain reward pathways are not blocked by the cannabinoid antagonist and suggest that a CB-1 antagonist may be 

able to selectively block relapse provoked by cocaine cues 

or the drug itself without producing unpleasant effects 

such as a general loss of ability to feel pleasure.

The CB-1 antagonist’s failure to block relapse triggered 

by the footshock stressor suggests that the neurobiological 

mechanisms of stress-induced reinstatement of cocaineseeking are different from those of drug- and cue-induced 

reinstatement, says Dr. Shaham, who led this portion of 

the study. Studies by Dr. Shaham, Dr. Jane Stewart of 

Concordia University in Montreal, and Dr. Lin Lu of 

Shanghai Medical University indicate that stress-induced 

relapse is precipitated through activation of specific 

neurotransmitters in the brain that regulate the body’s 

response to stressful situations. Compounds that block the 

release of these brain neurotransmitters or their action on 

their receptors have been shown to block stress-induced 

but not cue- or drug-induced reinstatement of cocaineseeking. 

With this new study, researchers have now identified 

underlying biological mechanisms involved in three of the 

most common precipitators of relapse to drug use, as well 

as compounds that effectively deactivate those mechanisms. 

“The next step would be to evaluate whether a CB-1 

antagonist could be used in combination with agents that 

block the release of stress neurotransmitters as relapseprevention medications,” Dr. De Vries says. 

Sources

• De Vries, T.J.; Shaham, Y.; et al. A cannabinoid 

mechanism in relapse to cocaine-seeking. Nature 

Medicine 7(10):1151–1154, 2001.

• Shalev, U.; Grimm, J.W.; and Shaham, Y. 

Neurobiology of relapse to heroin and cocaine-seeking: 

A review. Pharmacological Reviews 54:1–42, 2002. 
Research Findings

94

Cocaine’s Effects on Cerebral Blood Flow Differ Between 

Men and Women

By Jill S. Williams, NIDA NOTES Contributing Writer 

Researchers studying the effects of cocaine on the brain 

have found that men and women with comparable drug 

use histories do not exhibit comparable damage. One 

study showed that women suffered less neuronal injury 

than men; another, that cocaine-dependent women have 

fewer abnormalities in blood flow to the brain than do 

cocaine-dependent men. Now, a recent NIDA-funded 

study has taken an important step toward explaining these 

differences between the sexes.

Cocaine constricts blood vessels, temporarily narrowing 

arteries and reducing blood flow to the brain, heart, and 

other areas of the body. Repeated exposure to cocaine can 

lead to blood-flow deficits in the brain that persist long 

after cocaine use has ended, causing permanent damage.

Dr. Marc J. Kaufman and colleagues at McLean Hospital, 

Harvard Medical School, in Belmont, Massachusetts, 

found that cerebral blood flow during the follicular phase 

of women’s menstrual cycles (days 1 through 14, prior 

to ovulation) is not affected by exposure to cocaine. In 

women during their luteal phase (after ovulation, typically 

days 15 through 28) and in men, cocaine restricts cerebral 

blood flow.

“We hypothesized that the differences in blood flow 

might be caused by sex hormones,” says Dr. Kaufman. 

“We decided to investigate whether women with high levels of estrogen, which improves blood-vessel elasticity, are 

more resistant to the vasoconstrictive effects of cocaine.”

Dr. Kaufman and his colleagues used dynamic susceptibility 

contrast magnetic resonance imaging (DSC MRI) to study 

cocaine-induced changes in cerebral blood volume in 13 

healthy young women (average age 28) with histories of 

occasional cocaine use. The women’s self-reported lifetime 

cocaine use averaged 13 exposures (ranging from 1 to 40). 

Each woman was given a dose of cocaine and underwent 

a DSC MRI scan of cerebral blood volume during both 

phases of her menstrual cycle. During the first part of the 

menstrual cycle, estrogen levels are high and progesterone 

levels are low; during the second part, progesterone levels 

rise. In each imaging session, two brain images were collected: one as a baseline measure of cerebral blood volume 

and the second 10 minutes after cocaine administration.

The study found no significant changes in cerebral blood 

volume after cocaine administration during the women’s 

follicular phase. During the luteal phase, when progesterone levels are highest, the women’s cerebral blood flow 

fell approximately 10 percent after cocaine administration. 

These data compare to Dr. Kaufman’s findings in a similar 1998 study, that men experience, on average, a 20-percent reduction in cerebral blood volume after cocaine 

administration.

“We found what we were expecting,” says Dr. Kaufman. 

“There was a minimal change in follicular cerebral blood 

volume, attributable, we believe, to the protective effects 

of estrogen. The greater vasoconstrictive effect of cocaine 

in luteal-phase women may be attributable to the 

progesterone, which has been shown to increase cocaine’s 

vascular toxicity.”

Volume 17, Number 2 (May, 2002)

Magnetic resonance (MR) image intensity was measured to compare the hemodynamic effects of cocaine during two phases of a 

woman’s menstrual cycle. Following cocaine administration during 

the follicular phase, image intensity was relatively high, reflecting 

cerebral blood flow at 97 percent of its pre-cocaine baseline. When 

the drug was given during the luteal phase, lower image intensity 

reflected a fall in blood flow to 82 percent of baseline.

Cocaine’s Effect on Cerebral Blood Volume 

Varies Throughout Menstrual Cycle
95

Dr. Kaufman’s next step will be to administer estrogen or 

progesterone to men and luteal-phase women and measure the effects on cerebral blood volume after cocaine 

administration. The ultimate goal will be to develop a 

hormonelike medication to counteract the vascular effects 

of cocaine. 

“Beyond confirming that cocaine does have a damaging 

effect on the brain and is not safe to use, this research 

contributes to our understanding of the drug’s deleterious 

effects,” says Dr. Steven Grant, of NIDA’s Division of 

Treatment Research and Development. “Additionally, the 

research points out that we’ve got to stop thinking of both 

sexes as the same when it comes to the effects of drugs. 

Dr. Kaufman has shown that cocaine affects men and 

women differently.”

Sources

• Kaufman, M., et al. Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual 

cycle phase. Biological Psychiatry 49(9):774–781, 2001. 

• Kaufman, M., et al. Cocaine decreases relative cerebral 

blood volume in humans: A dynamic susceptibility 

contrast magnetic resonance imaging study. 

Psychopharmacology 138:76–81, 1998. 

A sequence of magnetic resonance images taken at 1-second intervals after a woman received an intravenous blood marker progresses from 

light to dark to light as her cerebral blood flow carries the marker into her brain and washes it back out again. The total marker present in 

all the images, measured as their intensity (darkness), reflects total cerebral blood volume. To study the hemodynamic effects of cocaine, investigators compared two such sequences, obtained before and after administration of the drug, during each menstrual period.

Using Magnetic Resonance Imaging (MRI) To Track Cerebral Blood Volume
96

Blood Pressure Medication May Improve Cocaine Treatment 

Results in Patients With Severe Withdrawal Symptoms

By Robert Mathias, NIDA NOTES Staff Writer

Volume 16, Number 6 (February, 2002)

A medication used to treat high blood pressure may be an 

effective add-on therapy for cocaine-dependent patients 

who suffer severe withdrawal symptoms when they stop 

using the drug, a NIDA-funded study indicates. Patients 

who experienced severe anxiety and other symptoms and 

were treated with the medication—propranolol—stayed in 

treatment longer and used less cocaine than a comparable 

group of patients who were treated with a placebo, the 

study shows.

Cocaine-dependent patients who experience severe withdrawal symptoms generally use cocaine heavily and are 

more dependent on the drug than patients who have less 

severe withdrawal symptoms. “These patients are unable 

to stop using the drug for significant periods and are more 

likely to drop out of treatment programs,” says Dr. Kyle 

Kampman of the University of Pennsylvania School of 

Medicine in Philadelphia, who conducted the study. “This 

is not a tiny subgroup. We’ve found that about 40 percent 

of the cocaine abusers who come into the Day Treatment 

Program of the Philadelphia Veterans Affairs Hospital 

have withdrawal severity scores that are high enough to 

put them at risk for doing poorly in treatment.”

Dr. Kampman and his colleagues theorized that propranolol might lessen the severity of symptoms such as anxiety 

and craving experienced by newly abstinent cocaine treatment patients. Propranolol belongs to a class of medications called beta-adrenergic blockers that inhibit the effects 

of adrenaline in the central and peripheral nervous systems, where it works to arouse the body’s “fight or flight” 

response to dangerous or stressful situations. Beta-andrenergic 

blockers have been used clinically to treat general anxiety and anxiety associated with alcohol withdrawal. The 

researchers thought propranolol’s tempering of symptoms such as palpitations and sweating might also reduce 

cocaine craving associated with such symptoms. 

In the study, the researchers used an interviewer-administered questionnaire, the cocaine selective severity assessment (CSSA), to measure cocaine withdrawal symptoms 

among 108 treatment-seeking cocaine-dependent men 

and women. The CSSA assesses the intensity of 18 symptoms including anxiety, cocaine craving, depressed mood, 

appetite changes, sleep disturbances, and altered heart 

rates that patients may experience when they stop using 

cocaine. In a previous study, the researchers found that 

patients who had high CSSA scores when they entered 

treatment were likely to drop out of treatment.

Following a 1-week lead-in period in which all subjects 

were given a placebo, researchers randomly assigned 

patients to receive either propranolol or a placebo daily 

for 8 weeks. All subjects also received cognitive-behavioral 

counseling twice a week. Urine tests for cocaine were conducted three times a week throughout the trial to assess 

cocaine use. Treatment retention, cocaine withdrawal 

symptoms, craving, mood, and anxiety symptoms were 

evaluated weekly. 

When the researchers analyzed results for all study subjects, they found that propranolol-treated subjects had less 

severe cocaine withdrawal symptoms during the trial, but 

they did not do significantly better on any other outcome 

measure than those treated with the placebo. However, 

Nearly 69 percent of cocaine treatment patients experiencing severe

withdrawal symptoms who received propranolol completed the 

treatment program, compared to 29 percent of patients with similar symptoms who were treated with a placebo.

Research Findings

Effect of Propranolol on Cocaine Treatment 

Retention In Patients With Severe 

Withdrawal Symptoms
97

when the researchers looked at outcomes in conjunction 

with the severity of cocaine withdrawal symptoms, they 

found that propranolol-treated individuals who had CSSA 

scores in the upper third of all subjects at baseline were 

much more likely to complete the treatment program 

than subjects with similar baseline CSSA scores who were 

treated with placebo. Among subjects with high CSSA 

scores, 69 percent of those who received propranolol 

completed treatment, compared to 29 percent of those 

treated with a placebo. Propranolol-treated high-CSSA 

subjects also had significantly lower urine levels of benzoylecognine, a cocaine metabolite, than did placebo-treated 

subjects, indicating they used less cocaine throughout the 

trial. There were no significant gender differences in any 

outcome measures.

Treatment and Research Implications

Although the study’s findings are preliminary, they suggest 

that propranolol may be a useful add-on treatment for the 

substantial subset of cocaine-dependent patients who have 

severe withdrawal symptoms. However, treatment outcomes in propranolol-treated subjects were still far from 

optimal. Additional medication or more intense counseling may be needed to treat such patients effectively, the 

researchers indicate. “Clinicians can use the CSSA score 

to predict treatment outcomes and try to match people to 

appropriate levels of treatment,” says Dr. Kampman. “If 

you put someone with a high score in once- or even twicea-week individual counseling, they just aren’t going to do 

well. They need more intensive treatment.” 

The study also has implications for researchers testing cocaine treatment medications, Dr. Kampman says. 

“Until now, clinical trials haven’t separated out those 

patients who need to be detoxified,” he says. “They come 

in with ‘hot’ urines [indicative of heavy, current cocaine 

use], have a lot of withdrawal symptoms, and have trouble 

getting abstinent. They are so different from people who 

enter treatment with cocaine-free urines and low withdrawal symptoms, that if you put the two groups together 

when you test a medication, you are going to miss significant treatment effects. In our studies, we are now dividing patients into two distinct populations based on initial 

assessment of the severity of their withdrawal symptoms. 

For patients who have a lot of withdrawal symptoms, we 

test medications that have the potential to reduce severity of these symptoms to see if it will help them get clean 

and stay in treatment. For patients who have few withdrawal symptoms and less difficulty achieving initial 

abstinence, we select a medication that might work better 

to prevent relapse.”

Additional Medications Research 

In addition to propranolol, Dr. Kampman has been testing the potential of other medications to improve treatment outcomes for cocaine-dependent patients with severe 

withdrawal symptoms. Results of a preliminary trial of 

amantadine, which may alleviate cocaine’s disruption of 

the brain’s dopamine system, were promising. Patients 

with severe cocaine withdrawal symptoms at the start of 

treatment used less cocaine during the trial than those 

who received a placebo. 

Following up on these results, Dr. Kampman and his 

colleagues now are conducting a large, double-blind prospective study of the effectiveness of amantadine and propranolol individually and in combination. The study 

is targeted specifically at cocaine-dependent patients who 

score in the upper one-third of patients on the CSSA.

“We know that amantadine slightly increases the release 

of dopamine, which in turn might reduce the dysphoria—

the pervasive unhappiness and restlessness—that also 

is associated with cocaine withdrawal,” says Dr. Maria 

Majewska of NIDA’s Division of Treatment Research and 

Development. “If amantadine can reduce dysphoria and 

propranolol can reduce the anxiety and the arousal associated with craving, maybe this will be a winning combination with this population. We are cautiously optimistic as 

we await the results of the trial.” 

Sources 

• Kampman, K.M., et al. Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment. Psychology of Addictive Behaviors 15(1):52–59, 

2001.

• Kampman, K.M., et al. Effectiveness of propranolol 

for cocaine dependence treatment may depend on 

cocaine withdrawal symptom severity. Drug and 

Alcohol Dependence 63(1):69–78, 2001. 

• Kampman, K.M., et al. Amantadine in the treatment 

of cocaine-dependent patients with severe withdrawal 

symptoms. American Journal of Psychiatry

157(12):2052–2054, 2000. 
Research Findings

98

Methamphetamine, Cocaine Abusers Have Different Patterns of 

Drug Use, Suffer Different Cognitive Impairments

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 16, Number 5 (December, 2001)

NIDA-supported research has found that methamphetamine abusers typically use the drug throughout the day in 

a pattern that resembles taking medication, while cocaine 

abusers often exhibit a binge pattern, using the drug continuously over a period of several evening and nighttime 

hours. And, according to the researchers at the University of 

California, Los Angeles (UCLA), the drugs appear to cause 

different types of deficits in reasoning and concentration.

Patterns of Use

Dr. Sara Simon and her UCLA colleagues interviewed 

120 methamphetamine abusers and 63 cocaine abusers 

to determine patterns of drug use. Ninety-seven of the 

methamphetamine abusers and 56 cocaine abusers were 

recruited from treatment programs; the others were currently using the drug and not seeking treatment.

Continuous use—more than 20 times per month—was 

more common for both cocaine abusers (52 percent) and 

methamphetamine abusers (70 percent) than was any 

other pattern of drug use. Among those who used either 

drug fewer than 20 times per month, methamphetamine 

abusers were 4 times as likely as cocaine abusers (48 percent compared with 12 percent) to use the drug at least 

once per week in a regular cycle.

“The typical methamphetamine abuser reported using 

the drug when he or she first got up in the morning, 

then using approximately every 2 to 4 hours during their 

waking day. Most of the descriptions of use more closely 

resembled taking a medication than using a drug for pleasure,” Dr. Simon says. “Cocaine abusers reported patterns 

that fit a picture of recreational use: They began in the 

evening and continued until all the cocaine on hand had 

been used.” 

The different patterns of use may in part be a result of the 

drugs’ different effects in the body, the researchers say: 

Methamphetamine triggers the release of large amounts of 

the neurotransmitter dopamine into areas of the brain that 

regulate feelings of pleasure, whereas cocaine blocks the 

removal of dopamine, resulting in an accumulation that 

causes continuous pleasurable stimulation of brain cells. 

The effects of methamphetamine typically last more than 

10 hours, and the half-life (the time it takes for the body 

to remove 50 percent of the drug) of methamphetamine 

is 12 hours. Cocaine’s half-life is roughly 1 hour, and the 

drug’s high lasts about 20 to 30 minutes.

Understanding the patterns of use for methamphetamine 

and cocaine will help treatment providers and drug users 

identify circumstances that may lead to relapse to drug 

use. “Differences in use patterns indicate different triggers 

and different times and places when the recovering abuser 

is particularly vulnerable,” says Dr. Simon.

Effects on Reasoning and Memory

In another study, Dr. Simon and her colleagues evaluated 

the effects of methamphetamine and cocaine on learning and memory in 40 methamphetamine abusers and 40 

cocaine abusers who were not in treatment and 80 individuals who had never used either stimulant drug. The 

researchers administered tests to evaluate memory, perceptual speed and ability to manipulate information, ability to ignore irrelevant information, general intelligence, 

verbal fluency, and executive function (abstract reasoning, 

reactive flexibility, and ability to use feedback).

Methamphetamine abusers performed more poorly than 

nonusers of stimulants in tests of word recall, perceptual 

speed, ability to manipulate information, and abstract 

thinking. Cocaine abusers scored more poorly than nonusers of stimulants in tests measuring ability to recall words 

and pictures and working memory.

“Methamphetamine abusers displayed impairments on the 

tests of perceptual speed and manipulation of information 

that were not seen in the cocaine group. Moreover, in 

tests that require both speed and manipulation, there was 

even more difference between the groups than on tests of 

either skill separately,” Dr. Simon says.

“Overall, both drugs are associated with similar cognitive 

deficits,” Dr. Simon says. “The most striking difference 

is that methamphetamine abusers have more trouble than 

cocaine abusers at tasks requiring attention and the ability 

to organize information.”
99

Sources

• Simon, S.L., et al. A comparison of patterns of 

methamphetamine and cocaine use. Journal of 

Addictive Diseases 21(1):35–44, 2002.

• Simon, S.L., et al. Cognitive performance of current 

methamphetamine and cocaine users. Journal of 

Addictive Diseases 21(1):61–74, 2002. 
Research Findings

100

Altered Cellular Activity May Be First Step in Progression to 

Cocaine Addiction

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 16, Number 5 (December, 2001)

NIDA-supported research has identified a neurobiological mechanism that could be involved in initiating the 

compulsive drug-seeking behavior that is the behavioral 

hallmark of cocaine addiction. Scientists have shown that, 

in mice, a single exposure to cocaine induces changes in 

brain cells that are very similar to long-term potentiation, 

a process that plays an important role in associating experiences with feelings and motivation.

When a stimulus induces long-term potentiation in a cell, 

the cell will respond more strongly to future exposures to 

the same stimulus. Using mice, Dr. Robert Malenka of 

Stanford University in Palo Alto, California, along with 

Dr. Antonello Bonci and his colleagues at the University 

of California, San Francisco, showed that cocaine induces 

this effect on dopamine (DA) cells in the brain’s ventral 

tegmental area (VTA). When stimulated by cocaine, these 

mouse cells release the neurotransmitter DA, a brain 

chemical that leads to feelings of pleasure. By increasing 

the responsiveness of the VTA DA cells, cocaine-induced 

potentiation could create powerful associations between 

drug taking, the situations in which drugs are taken, and 

feelings of pleasure.

To assess the effect of cocaine, Drs. Malenka and Bonci 

measured the electrical currents generated in VTA DA 

cells by activation of structures known as AMPA receptors—sites that, along with NMDA receptors respond to 

another neurotransmitter, glutamate. In general, the more 

current that flows through a cell’s AMPA receptors, the 

more DA the cell will release. The researchers showed that 

exposure to a dose of cocaine (15 mg/kg of body weight) 

comparable to doses used by humans caused a higher 

current to flow through AMPA receptors; consequently 

the VTA neurons would be expected to release DA more 

abundantly.

“A single injection of cocaine more than doubles the 

activation of the dopamine cells. The changes were still 

present 5 days later, but not 10 days after injection,” 

Dr. Malenka says. “This finding alone does not explain 

cocaine’s ability to produce compulsive drug-seeking 

behavior. But for the first time it describes how cocaine 

can trigger a mechanism that contributes a small but 

important part of the complex cascade of events that 

leads to addiction.”

“Two aspects of this study have particular significance,” says 

Dr. Susan Volman of NIDA’s Division of Neuroscience 

and Behavioral Research. “First, the effect was obtained 

with a single dose of cocaine. Second, the effects of 

Long-Term Potentiation in Dopamine Cells

When the brain chemical glutamate reaches dopamine cells in the 

ventral tegmental area, it activates specific sites called NMDA 

receptors and AMPA receptors. Electrical current generated by 

the AMPA receptors triggers the release of dopamine, a chemical 

associated with the pleasurable effects of addictive drugs. Release of 

dopamine is enhanced by a condition called long-term potentiation 

(LTP), which is thought to play a role in associative learning and

memory formation. When LTP has been established a glutamate 

stimulus results in higher AMPA currents; therefore, the cell is likely to release dopamine more abundantly than it would have previously. NIDA-supported researchers have found that a single exposure to cocaine can establish LTP in mice, and that the enhanced 

activity lasts for more than 5 days.

Effect of Cocaine Exposure on Dopamine Cells

Mice injected with a single dose of cocaine exhibited a higher ratio 

of AMPA to NMDA currents—an indication of long-term potentiation—in dopamine cells in the ventral tegmental region 1 day and 

5 days after the drug exposure. Mice injected with saline showed no long-term potentiation.
101

cocaine were indistinguishable from long-term potentiation, which suggests that, for nearly a week after it is 

administered, cocaine utilizes the cellular mechanism 

involved in normal adaptive learning.” By forging associations between experiences and positive or negative feelings, long-term potentiation of DA and other types of 

brain cells is a key mechanism in learning and memory 

and, in this way, has an impact on future behavior.

Source

• Ungless, M.A.; Whistler, J.L.; Malenka, R.C.; and 

Bonci, A. Single cocaine exposure in vivo induces 

long-term potentiation in dopamine neurons. 

Nature 411:583–587, 2001. 
Research Findings

102

Biochemical Brain Abnormality Found in School-Age Children 

Prenatally Exposed to Cocaine

By Robert Mathias, NIDA NOTES Staff Writer

Volume 16, Number 4 (October, 2001)

Exposure to cocaine before birth may affect the way a 

child’s brain functions many years later, according to a 

recent NIDA-funded study. The brain-imaging study 

found a chemical abnormality in the brains of 8-year-old 

children that may reflect alterations in metabolic processes 

that enable brain cells to use energy and function properly, the researchers say. 

“These children were exposed to cocaine only during 

gestation and their brains have had 8 years to recover 

from that exposure,” says Dr. Joseph Frascella of NIDA’s 

Division of Treatment Research and Development. “It is 

surprising that they are still showing these deficits so many 

years later.” The new finding suggests that early exposure 

to drugs has more long-lasting effects on the brain than 

previously thought, he notes.

The nature and extent of possible developmental damage 

to infants and children from prenatal exposure to cocaine 

has been the subject of much apprehension and scientific 

study. In the 1980s, anecdotal reports of abnormalities 

among cocaine-exposed children contributed to fears 

that these children were irreparably damaged and would 

never be able to function in society. Subsequent scientific research has dispelled such exaggerated concerns for 

the vast majority of prenatally exposed children. NIDAfunded studies that have been tracking the development 

of groups of cocaine-exposed babies through adolescence 

now indicate that most seem to function normally, but 

some may have subtle impairments in their ability to control emotions and focus attention that could put them at 

risk of behavioral and learning difficulties. 

Previous brain-imaging studies of children prenatally 

exposed to cocaine have yielded conflicting information 

about the drug’s effects on the developing central nervous 

system. Some studies have found abnormalities in brain 

structure, while others have not. Studies in abstinent adult 

cocaine abusers, using an imaging technique called magnetic resonance spectroscopy (MRS), have suggested that 

chronic cocaine use may cause persistent damage to neurons in the frontal lobes of males and that brain metabolic 

abnormalities also could exist despite a normal-appearing 

brain structure. Dr. Lynne Smith of the Harbor-UCLA 

Medical Center in Torrance, California, and Dr. Linda 

Chang of Brookhaven National Laboratory, in Upton, 

New York, used this MRS technique to see if similar biochemical abnormalities might be present in the brains of 

children who had been prenatally exposed to cocaine, even 

if they appeared to have no structural damage.

The researchers used magnetic resonance imaging (MRI) 

to assess brain structure and MRS to examine brain biochemistry in 14 8-year-old children who had been exposed 

to cocaine in the womb. They administered the same 

brain scans to a control group of 12 age-matched, nonexposed children. The MRS scans measured levels of various 

chemicals in different brain regions. Increased or reduced 

concentrations of these chemicals can indicate either damage to nerve cells or alterations in brain cell function in 

these regions. The researchers assessed a frontal area of the 

brain, made up of “white matter,” which consists mainly 

of nerve fibers and specialized support cells. They also 

looked at an area deep in the brain called the basal ganglia, which contains clusters of nerve cell bodies, or 

“gray matter.” 

The study found no difference between the exposed 

and nonexposed children in concentrations of N-acetylaspartate (NAA), a nerve cell metabolite, in either the 

frontal area or the basal ganglia. Because NAA levels are 

markers for the density and integrity of nerve cells, the 

Creatine Level Alterations in Frontal White Matter of 

Cocaine-Exposed Children 

MRS scans suggest cocaine-exposed children did not have significant nerve damage or loss in the brain regions that were examined. 

However, cocaine-exposed children had significantly higher levels of 

the brain metabolite creatine than nonexposed children in a frontal 

area of the brain made up of “white matter,” which consists mainly 

of nerve fibers and specialized support cells. The abnormality may 

reflect alterations in metabolic processes that enable brain cells to 

use energy and function properly. 
103

normal NAA found in children prenatally exposed to cocaine 

suggests they did not have significant nerve damage or 

loss in the two brain regions that were examined. The MRI 

evaluations also showed no brain structure abnormalities 

in children in either group. However, cocaine-exposed 

children had significantly higher levels of creatine in the 

white matter of the frontal lobes than nonexposed children. Elevated creatine levels indicate that the brain cells 

of cocaine-exposed children use energy differently in this 

region.

“All brain cells require creatine for all functions,” says Dr. 

Chang. “The altered creatine levels we found could affect 

how both nerve cells and support cells are functioning in 

the brain. We also have found the same abnormal creatine 

levels in frontal white matter in adult cocaine abusers 

more than a year after they have stopped using cocaine. 

The drug seems to have a particularly long-lasting effect 

on energy metabolism in this brain area that merits further investigation.” 

“The frontal area of the brain is involved in our ability to 

control impulses and sustain attention on a task,” notes 

Dr. Frascella. Thus, it is possible that the altered brain 

function found in this area could be a biological basis for 

findings from other research that some cocaine-exposed 

children are more impulsive and easily distracted than 

their peers. However, additional research is needed to 

make this determination, he says.

Sources

• Chang, L.; Ernst, T.; Strickland, T.; and Mehringer, 

C.M. Gender effects on persistent cerebral metabolic 

changes in the frontal lobes of abstinent cocaine users. 

American Journal of Psychiatry 156(5):716–722, 1999.

• Chang, L., et al. Neurochemical alterations in asymptomatic abstinent cocaine users: A proton magnetic 

resonance spectroscopy study. Biological Psychiatry

42(12):1105–1114, 1997.

• Smith, L.M.; Chang, L.; et al. Brain proton magnetic 

resonance spectroscopy and imaging in children 

exposed to cocaine in utero. Pediatrics 107(2):227–

231, 2001. 
Research Findings

104

Even Modest Cocaine Use May Cause Brain Changes That 

Could Contribute to Addiction

By Robert Mathias, NIDA NOTES Staff Writer 

Volume 16, Number 3 (August, 2001)

A major goal of drug abuse research is to determine how 

voluntary drug use turns into compulsive drug use and 

addiction. A recent NIDA-supported study sheds light on 

drug-induced brain changes that may play an important 

role in this process. The study, conducted in rhesus monkeys, found that even a single low dose of cocaine reduced 

the brain’s response to an identical dose of the drug taken 

later in the same day. Conversely, weekly exposure to 

low doses of cocaine made the monkeys’ brains progressively more sensitive to the drug. These findings suggest 

that even occasional cocaine use can alter brain function 

in ways that may put voluntary users at increased risk of 

addiction.

“Perhaps the most striking aspect of this study is the 

relatively low drug exposure—in each session and cumulatively over the course of the study—that resulted in 

progressive changes in brain response,” says Dr. Charles 

Bradberry of Yale University School of Medicine in West 

Haven, Connecticut, who conducted the study. “Previous 

research in rats indicates that these changes in brain function are essentially permanent and may contribute to 

cocaine use becoming compulsive,” he says. Characteristic 

patterns of human cocaine consumption in which cocaine 

is taken repeatedly can result in much higher levels of 

exposure and could lead to more pronounced changes in 

brain function, Dr. Bradberry adds.

The study assessed changes in brain function in four 

rhesus monkeys that were permitted to take a maximum 

of two doses of 0.5 mg of cocaine per kilogram of their 

body weight once a week for 6 months. A previous study 

conducted by Dr. Bradberry indicated that the 0.5 mg/kg 

dose produces blood levels of cocaine in the monkeys that 

are equivalent to those found in humans who experience 

euphoria when given cocaine in laboratory settings. The 

monkeys self-administered each dose by pressing a lever 

when a light indicated that cocaine was available. The weekly 

self-administration of low doses of cocaine was designed to 

simulate human patterns of weekend cocaine use.

Each week, the researchers measured extracellular levels 

of dopamine in a region of the monkeys’ brains that corresponds to the limbic system in human brains. Cocaineinduced dopamine increases in this region are thought 

to trigger euphoria and play a significant role in cocaine 

abuse and addiction.

Short-Term Brain Changes

Within each weekly session, the researchers measured 

the monkeys’ extracellular dopamine levels after the initial dose of cocaine. When the monkeys’ extracellular 

dopamine returned to pre-cocaine levels, the researchers 

Acute Tolerance 

Acute Tolerance—Exposure to a single low dose of cocaine made 

the monkeys’ brains less responsive to a subsequent dose of the drug 

taken shortly thereafter, a phenomenon called acute tolerance. This 

illustration shows extracellular dopamine levels in a monkey’s brain 

after it has self-administered two identical doses of cocaine. The second 

dose, taken after the effects of the first dose wore off, produced lower 

levels of dopamine.

“This rapid development of 

tolerance to cocaine’s effects could 

underlie the repeated consumption 

of escalating doses of the drug 

that is typical of human cocaine 

binge sessions.”
105

allowed the monkeys to administer the second dose of the 

drug. The dopamine level did not rise as much following 

the second dose. This phenomenon, where exposure to a 

drug makes the brain less responsive to a subsequent exposure shortly thereafter, is called acute tolerance.

“This rapid development of tolerance to cocaine’s effects 

could underlie the repeated consumption of escalating 

doses of the drug that is typical of human cocaine binge 

sessions,” Dr. Bradberry says. “Research we are conducting 

now suggests that this acute tolerance may be important 

in regulating how much cocaine someone takes in a given 

session.” Instead of limiting the monkeys’ cocaine intake, 

the new research permits the animals to continue to infuse 

cocaine after the first two doses. “Animals that show the 

most tolerance will take as much cocaine as they can as 

soon as it is available,” Dr. Bradberry says. “Animals that 

do not show as much tolerance don’t take as much.” 

Long-Term Brain Changes

The modest doses of cocaine once a week also caused 

long-lasting changes in the way the monkeys’ brains 

responded to the drug over time. As the study progressed, 

the same 0.5 mg/kg dose of cocaine that began each weekly 

session produced increasingly greater changes in the levels 

of extracellular dopamine in the monkeys’ brains than it 

did at the beginning of the study.

“This finding demonstrates for the first time that when 

primates are exposed to a pattern of occasional cocaine 

use, they develop neurochemical sensitization, a phenomenon marked by an increase in brain response following repeated administration of a drug,” says Dr. Jane 

Acri of NIDA’s Division of Treatment Research and 

Development.

“Our knowledge of exactly how people become addicted 

to drugs is in its early stages,” Dr. Acri says. “Now, we are 

trying to elucidate the factors involved in the transition 

from drug use to addiction. While it is still unclear how 

sensitization affects this transition, we think it may play a 

role. Demonstrating these initial changes in animals is a 

very big step in understanding this process from a biological 

point of view.”

Source

• Bradberry, C.W. Acute and chronic dopamine 

dynamics in a nonhuman primate model of 

recreational cocaine use. Journal of Neuroscience

20(18):7109–7115, 2000. 

Long-Term Sensitization

Long-Term Sensitization—Modest weekly exposure to cocaine 

gradually made the monkeys’ brains more responsive to the drug, a 

phenomenon called neurochemical sensitization. This illustration 

shows weekly changes in extracellular dopamine levels in a monkey’s 

brain after it has taken the first dose of cocaine in each session. In 

later weeks, the same dose of cocaine produces progressively higher 

levels of dopamine than it did in earlier weeks.
Research Findings

106

Cues for Cocaine and Normal Pleasures Activate Common 

Brain Sites

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 16, Number 2 (May, 2001)

Cocaine abusers may experience a powerful urge to take the 

drug when they encounter environmental cues such as people, 

places, or paraphernalia that they associate with drug use. 

This cue-induced craving may be accompanied by physical 

sensations—light-headedness, increased heart rate, or a mild 

drug-like “high”—like those produced by cocaine.

The similarity of cue-induced sensations to those of actual 

cocaine use suggests that some of the brain structures 

affected by cocaine are also affected by cocaine-related 

cues. Now, NIDA-supported research using two brain 

imaging techniques has shown that limbic regions of the 

brain, where cocaine is thought to produce its pleasurable 

effects by disrupting normal action of the brain chemical 

dopamine, also are activated by viewing videos containing 

cocaine-related scenes. Moreover, one study indicates that 

cues related to normal pleasures, such as sex, also activate 

the same sites.

Cocaine Cues Activate Sites in Limbic Region

At the University of Pennsylvania in Philadelphia, Dr. 

Anna Rose Childress and her colleagues used positron 

emission tomography (PET), which measures cerebral 

blood flow, to detect activation of nerve cells in the brain, 

to monitor the effect of cocaine-related cues on activity in 

limbic regions of the brain.

Participants in the study—14 adult male in-treatment 

cocaine users and 6 adult males who had never used 

cocaine—underwent PET imaging while watching a 

25-minute video that contained images and sounds of 

simulated purchase, preparation, and smoking of crack 

cocaine. During the same imaging session, the participants 

watched a 25-minute nature travelog. Before and after 

watching each video, the men rated their feelings of druglike high, craving for drugs, relaxation or tension, and 

general sense of well-being. The cocaine group, but not 

the non-cocaine group, reported craving and a drug-like 

high during the drug-related video. The nature video produced no subjective drug-like sensations in either group.

“The cocaine video that induced drug craving was associated with increased activation of two of the brain’s limbic 

regions, the amygdala and the anterior cingulate, in the 

cocaine patients,” Dr. Childress says.

Cocaine abusers showed increased limbic activation when 

watching the video containing cocaine-related scenes, but 

not when watching the nature video. The participants 

who had never used cocaine showed no limbic activation 

when viewing either the cocaine-related or nature video.

“Activation of these two limbic regions during cueinduced craving is consistent with the role they play in 

mood, emotional response, and reward learning,” Dr. 

Childress says. The regions also play a part in establishing 

associations between environmental signals and biologically 

significant stimuli such as food, sexual partners, and pain, 

Dr. Childress says, and are linked to the nucleus accumbens, a brain structure involved in associating behaviors 

and pleasurable rewards. “The interconnectedness of these 

regions makes it possible to experience the pleasures of 

rewards and to recognize opportunities to obtain them,” 

she says. If common sites are involved in both normal 

and drug-related stimulus and response, this could pose 

problems for some potential pharmacological approaches 

to treating cocaine addiction, according to Dr. Childress. 

“Medications designed to block the limbic activation 

might reduce cocaine craving, but patients might be less 

likely to take the medication if it also blunts mood and 

motivation,” she says.

Positron emission tomography shows that limbic regions in the 

brains of in-treatment cocaine users are activated by watching 

cocaine-related videos. Watching videos of nature scenes does not 

result in activation of these regions. This suggests that cue-induced 

craving for cocaine reflects activity in specific regions of the brain. 

(Greater activation is denoted by shades at the top end of the scale to 

right.)
107

Cues for Cocaine and Sex Act On Same Sites

At the Medical College of Wisconsin in Milwaukee, Dr. 

Elliot Stein and his colleagues used functional magnetic 

resonance imaging (fMRI), which measures blood oxygen 

levels, to show that the same limbic regions activated by 

cocaine and cocaine-related videos also are activated by 

videos containing scenes of normal nondrug stimulus. 

In this study, 31 adult males—17 cocaine users and 14 

nonusers—watched 4-minute films depicting either drug 

use, nature scenes, or explicit sexual activity. Participants 

completed brief questionnaires describing their reactions 

to each film.

Cocaine users reported craving while viewing the film 

depicting drug use, and fMRI data revealed increased 

activation of sites in the limbic and other regions of their 

brains. These regions showed far less activation in nonusers viewing the same film. Both groups reported excitement while watching the sex film, although the levels of 

excitement were lower for drug users. Imaging revealed 

similar patterns of brain activation in both groups while 

watching the sex video, with less intense activation among 

drug users. There were no differences between users and 

nonusers when viewing the nature film.

“Most of the brain regions identified through fMRI as 

cocaine craving sites were similarly activated by the sexual 

stimulus. This suggests that common brain circuits are 

involved in response to drug and nondrug arousing stimuli,” 

Dr. Stein says. “The fact that cocaine users’ brains exhibited 

relatively weak activation in response to the sex film suggests 

that cocaine craving does not merely act on the brain’s 

reward circuits, but also takes over these sites and in 

essence rewrites normal emotionally driven preferences,” 

Dr. Stein says.

The fact that cocaine cues seem to act on brain sites 

associated with emotional response, information processing, 

and working memory may be relevant to development of 

treatment approaches. “On an optimistic note, it suggests 

that what we know about normal learning, memory, and 

emotions could be usefully applied to cue-induced craving and the development of appropriate pharmacological, 

behavioral, and cognitive therapies,” Dr. Stein says.

Sources

• Childress, A.R., et al. Limbic activation during 

cue-induced cocaine craving. American Journal of 

Psychiatry 156(1):11–18, 1999. 

• Garavan, H.; Pankiewicz, J.; Bloom, A.; Cho, J-K.; 

Sperry, L.; Ross, T.J.; Salmeron, B-J.; Risinger, R.; 

Kelley, D.; Stein, E.A. Cue-induced cocaine craving: 

Neuroanatomical specificity for drug users and drug 

stimuli. American Journal of Psychiatry 157(11):1789–

1798, 2000. 

“Cocaine craving does not merely 

act on the brain’s reward circuits, 

but also takes over these sites and 

in essence rewrites normal 

emotionally driven preferences.” 

Functional magnetic resonance imaging shows activation of the 

same brain sites in cocaine addicts watching a cocaine-cravinginducing film (left) and non-drug-using subjects watching a film

depicting explicit sexual scenes (right). This suggests that cueinduced cocaine craving and sexual excitement are associated with 

the same brain sites.
Research Findings

108

Alcohol-Treatment Medication May Help Reduce Cocaine Abuse 

Among Heroin Treatment Patients

By Robert Mathias, NIDA NOTES Staff Writer 

A NIDA-supported study has found evidence that combining disulfiram, a medication long used to treat alcohol 

addiction, with buprenorphine, a new opiate-addiction 

treatment medication awaiting approval by the Food and 

Drug Administration (FDA), can reduce cocaine abuse 

among the more than 50 percent of heroin-addicted 

individuals who also abuse cocaine. In the study, patients 

addicted to both opiates and cocaine who were treated 

with a combination of disulfiram and buprenorphine 

achieved 3 weeks of continuous abstinence from cocaine 

faster and stayed abstinent longer than those who received 

only buprenorphine.

“This study provides evidence that this well-established 

treatment for alcoholism, disulfiram, works with the 

newest opiate treatment medication, buprenorphine, 

to reduce cocaine abuse in opiate addicts,” says Dr. 

Tony George of Yale University Medical School in New 

Haven, Connecticut, one of the study’s investigators. 

“Buprenorphine is expected to be used widely to treat 

heroin addiction once it is approved by FDA. If additional 

research confirms our results, disulfiram may be a useful adjunct to buprenorphine for physicians to use with 

patients who also abuse cocaine,” he says.

In the study, which was led by Dr. Richard Schottenfeld, 

also of Yale, 20 patients addicted to heroin and cocaine 

were treated with buprenorphine for their opiate addiction. Eleven of these patients were randomly assigned to 

receive disulfiram also, and nine to get placebo pills. Of 

the 15 patients who completed the 12-week study, the 8 

disulfiram-treated patients were abstinent from cocaine 

for 7.8 weeks compared to 3.3 weeks of abstinence for the 

7 placebo-treated patients. Nearly half of the patients in 

both groups achieved 3 weeks of continuous abstinence, 

but disulfiram-treated patients achieved that measure after 

24.6 days, less than half the 57.8 days it took placebotreated patients. Opiate use declined in both groups with 

no significant differences between disulfiram and placebotreated groups over the course of the study.

Disulfiram and Cocaine, Alcohol, and Heroin Addiction

The findings from this study join a growing body of 

evidence from other Yale studies in recent years that disulfiram may reduce cocaine abuse among patients who also 

are addicted to alcohol or heroin, says 

Dr. Schottenfeld. 

Initially, scientists 

began to look at 

whether disulfiram 

would reduce 

cocaine use because 

of the medication’s 

known aversive 

effects on alcohol, he 

explains. Marketed 

as Antabuse, disulfiram has been used 

by physicians for 

more than 40 years 

to treat alcoholism. 

Patients who drink 

alcohol while on this 

medication can 

experience unpleasant 

reactions such as 

nausea, vomiting, 

and flushing.

Initial studies at Yale indicated that disulfiram decreases 

abuse of both cocaine and alcohol in patients who abuse 

both substances. Those findings are being tested now in 

a NIDA-funded study at the University of Pennsylvania 

in Philadelphia. Results from the Philadelphia study 

could provide independent confirmation of the Yale findings and yield additional information about the strong 

link between alcohol and cocaine use, says Dr. Maria 

Majewska of NIDA’s Division of Treatment Research and 

Development. “Some 70 to 80 percent of cocaine-dependent 

individuals also abuse alcohol,” she notes.

Last year, Yale researchers found that disulfiram also 

reduces cocaine use among opiate-dependent methadone 

treatment patients who use very little alcohol. “Since the 

opiate addicts in our new study also used little alcohol, 

these two studies suggest that disulfiram may be reducing 

cocaine use directly and not as a result of its effects on 

alcohol use,” Dr. George says.

Volume 16, Number 1 (March, 2001)

Total Weeks Abstinent 

From Cocaine 

During 12-Week Trial

Disulfiram-treated patients averaged 

more than twice as many weeks of 

abstinence from cocaine as placebotreated patients during the course of the 

12-week trial.
109

Exploring How Disulfiram Works

While the main goal of disulfiram research now under 

way is to confirm disulfiram’s efficacy in treating cocaine 

abuse, researchers also are seeking to increase understanding about how disulfiram works to inhibit this abuse. 

Understanding this process could lead to development of 

a new class of cocaine treatment medications that would 

better target this mechanism with increased efficacy and 

reduced adverse effects. 

Disulfiram may exert its anticocaine effects by increasing 

levels of the brain chemical dopamine through blocking 

the activity of an enzyme called dopamine-b-hydroxylase 

(DBH) that metabolizes the brain chemical dopamine. 

Since cocaine also boosts dopamine activity in the brain, 

the combination of disulfiram and cocaine may raise 

dopamine to excessive levels, producing a reaction that 

increases unpleasant effects associated with cocaine, such 

as anxiety and paranoia, Dr. Schottenfeld hypothesizes. 

This hypothesis is supported by laboratory studies at Yale 

in which disulfiram-treated patients had a more sustained 

physiological response to cocaine and reported that they 

experienced unpleasant, often anxiety-related, effects from 

it, he says.

Additional evidence that DBH may play a role in producing aversive reactions to cocaine comes from recent 

genetic studies at Yale led by Dr. Joseph Cubells. Dr. 

Cubells found that cocaine-abusing patients whose genetic 

makeup predicts low levels of DBH were much more 

paranoid than those with genes predicting high DBH 

activity. “The more frequent occurrence of this paranoia 

in low-DBH individuals may result from cocaine interacting with their genetic makeup to produce some form of 

functional hyperstimulation of their dopamine systems,” 

Dr. Schottenfeld says.

Disulfiram may curb cocaine use through a DBHmediated increase in dopamine levels in two slightly 

different but related ways, says Dr. Schottenfeld. When 

people stop using cocaine they may experience a decline in 

dopamine function and crave the drug to compensate for 

this reduction, he says. “In the absence of cocaine, disulfiram may increase dopamine levels sufficiently to reduce 

the drive to use cocaine,” he says. “However, if a patient 

on disulfiram slips and uses cocaine, the medication may 

make cocaine’s effects so unpleasant they deter further 

use.”

Sources

• Carroll, K.M.; Nich, C.; Ball, S.A.; McCance, E.; 

and Rounsaville, B.J. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. 

Addiction 93(5):713–727, 1998. 

• Cubells, J.F., et al. A haplotype at the DBH locus 

associated with low plasma dopamine beta-hydroxylase 

activity, also associates with cocaine-induced paranoia. 

Molecular Psychiatry 5(1):56–63, 2000. 

• George, T.P.; Chawarski, M.C.; Pakes, J.; Carroll, 

K.M.; Kosten, T.R.; and Schottenfeld, R.S. 

Disulfiram versus placebo for cocaine dependence in 

buprenorphine-maintained subjects: A preliminary 

trial. Biological Psychiatry 47(12):1080–1086, 2000.

• McCance-Katz, E.F.; Kosten, T.R.; and Jatlow, P. 

Disulfiram effects on acute cocaine administration. 

Drug and Alcohol Dependence 52(1):27–39, 1998. 

• Petrakis, I.L., et al. Disulfiram treatment for cocaine 

dependence in methadone-maintained opioid addicts. 

Addiction 95(2):219–228, 2000. 
110

Nicotine Craving and Heavy Smoking May Contribute to Increased 

Use of Cocaine and Heroin

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 15, Number 5 (October, 2000)

People who abuse drugs are also likely to be cigarette 

smokers. More than two-thirds of drug abusers are regular tobacco smokers, a rate more than double that of the 

rest of the population. NIDA researchers have found that 

craving for nicotine appears to increase craving for illicit 

drugs among drug abusers who also smoke tobacco, and 

this relationship suggests that smokers in drug treatment 

programs may be less successful than nonsmokers in 

staying off drugs.

At NIDA’s Intramural Research Program in Baltimore, 

Dr. Stephen Heishman and his colleagues examined the 

interaction of craving for nicotine and craving for other 

drugs and found that situations that increased desire 

to smoke also increased desire to use drugs. The study 

involved male and female adult smokers who were not trying to stop smoking and had histories of abusing alcohol, 

cocaine, heroin, marijuana, and/or other substances.

The researchers asked participants to listen to recorded 

scripts describing scenes and then to rate their urge to 

smoke and their desire to use other drugs. In the first part 

of the study, which involved 18 participants, the scripts 

had content that was generally pleasant (watching children 

on a sunny beach), unpleasant (a friend asking to borrow 

money), or neutral (doing household chores). Some scripts 

also included people expressing a desire to smoke, while 

others did not mention smoking at all (see “Cues Trigger 

Craving”). Both the scripts including a mention of smoking and those containing negative emotional content 

increased the participants’ craving for drugs, as well as 

for smoking.

In the second part of the study, 24 participants heard 

scripts with only pleasant content (enjoying the beach, 

talking on the phone with an old acquaintance, or visiting friends). These scripts also contained descriptions 

of tobacco craving that increased in intensity from no 

mention of smoking to asking the question, “How could 

you really enjoy yourself fully unless you were smoking?” 

Participants reported that craving for both drugs and 

tobacco increased as the intensity of the tobacco craving 

messages in the scripts increased.

“One of our more interesting findings was that scripts that 

elicited craving for tobacco also elicited craving for the 

subject’s drug of choice. This suggests that real-world situations that produce tobacco craving also may result in craving for drugs of abuse,” Dr. Heishman says. The findings 

also suggest that treatment for heroin, cocaine, or alcohol 

addiction might be more effective if it included concurrent 

treatment of tobacco addiction, he says.

In a NIDA-supported study at the University of California, 

San Diego, doctoral candidate Dominick Frosch and his 

colleagues at the Integrated Substance Abuse Program at 

the University of California, Los Angeles, investigated the 

relationship between levels of cigarette smoking and levels 

of cocaine and heroin use among 32 individuals who had 

been in a methadone treatment program for at least 4 months. 

The participants included 10 nonsmokers (6 female, 4 male) 

and 22 smokers (16 female, 6 male). The smokers were equally 

divided among heavy smokers (20 to 40 cigarettes per day) 

and “chippers” who smoked 5 or fewer cigarettes per day. 

“Compared with heavy smokers, chippers have less intense

Among patients in a methadone 

treatment program for opiate 

addiction, levels of cocaine or 

opiate use were directly related to 

levels of cigarette smoking.

Cigarette Smoking Associated With Use of Cocaine and Opiates
111

craving for their first cigarette of the day and can more 

comfortably avoid smoking in situations where it is not 

permitted,” Mr. Frosch explains.

The researchers evaluated the connection between tobacco 

smoking and illicit drug use among the smokers and 

nonsmokers by using breath and urine samples from the 

participants over a 7-day period. They found that the 

amount of cocaine and heroin use was closely related to 

the level of tobacco use. “The more cigarettes smoked, 

the more likely the person was to use illegal drugs,” Mr. 

Frosch says. “These findings provide compelling reasons 

for implementing smoking cessation programs for patients 

in methadone treatment, as the benefits of smoking cessation may extend to opiate addiction as well.” 

Sources

• Taylor, R.C.; Harris, N.A.; Singleton, E.G.; 

Moolchan, E.T.; and Heishman, S.J. Tobacco craving: intensity-related effects of imagery scripts in drug 

abusers. Experimental and Clinical Psychopharmacology

8(1):75–87, 2000.

• Frosch, D.L.; Shoptaw, S.; Nahom, D.; and Jarvik, 

M.E. Associations between tobacco smoking and illicit drug use among methadone-maintained opiatedependent individuals. Experimental and Clinical

Psychopharmacology 8(1):97–103, 2000. 

Cues Trigger Craving

To evaluate the impact of the urge to smoke on craving for other drugs, Dr. Stephen Heishman and his 

colleagues asked participants to rate their desires for 

tobacco and other drugs after listening to recorded 

“scripts” of scenes involving pleasant, unpleasant, or 

neutral situations and containing “urge” or “no-urge” 

smoking cues. The scripts were originally developed 

by Dr. Stephen Tiffany and colleagues at Purdue 

University. 

Pleasant, no-urge script: You’re at the beach, lying 

on a blanket. The warm sun penetrates your skin and 

relaxes you thoroughly. A fresh breeze blows over 

your body as you run your hands through the clean 

white sand and let the grains fall through your fingers. 

You’re feeling refreshed and at ease, and pleasant thoughts run through your mind. You can hear 

the sound of waves splashing rhythmically against 

the shore. Nearby there are some children playing a 

game. A bright red beach ball lands near your blanket. You look up and see two of the children running 

toward you to get their ball. You stand up, pick up the 

ball, and toss it to them. They laugh and giggle and 

run back to their game. You go to the blanket and lie 

down. You’re enjoying this day completely. 

Pleasant, urge script: You’re at a friend’s house sitting 

in a big comfortable chair. You’re with people you’ve 

known a long time, and you’re enjoying yourself very 

much. You’re sipping a drink, and you’re feeling totally 

at ease. 

Many of your friends are smoking cigarettes, just as 

you used to do. You’ve gone an entire week without 

smoking. As you sit there listening to the conversation 

and laughter, you begin to wonder what a cigarette 

would taste like. The more you think about smoking, 

the stronger your desire becomes. Maybe just tonight 

when you’re with your friends and having a good time, 

it would be okay to smoke. How could you really enjoy 

yourself fully unless you were smoking? Your desire 

to smoke becomes intense, and you know that there’s 

no good reason not to ask one of your friends for a 

cigarette

Sources

•	 Tiffany, S.T., and Drobes, D.J. Imagery and smoking urges: the manipulation of affective content. 

Addictive Behavior 15(6):531–539, 1990.

•	 Tiffany, S.T., and Hakenwerth, D.M. The production

of smoking urges through an imagery manipulation: Psychophysiological and verbal manifestations. Addictive Behavior 16(6):389–400, 1991.
112

Research Findings

Potential Cocaine Medications Show Effectiveness Against 

Psychosis, Seizures

By Steven Stocker, NIDA NOTES Contributing Writer 

Synthetic compounds that have shown promise for treating cocaine addiction also may be useful for treating 

phencyclidine (PCP)-induced psychotic reactions, schizophrenia, and cocaine-induced seizures and death, researchers have found. The compounds are called dopamine D3

receptor agonists, or D3

 agonists for short.

Dopamine is one of several chemicals called neurotransmitters that carry messages between the brain’s nerve cells, 

or neurons. After being released by a transmitting neuron, 

neurotransmitters interact with molecules called receptors 

on the surface of a receiving neuron, affecting the neuron’s activity. The combined activity of the brain’s neurons is responsible for all of the brain’s functions—such as 

feeling, thinking, and controlling movements—just as the 

combined electrical activity in a computer is responsible 

for all of the computer’s functions. At present, five types 

of dopamine receptors, designated D1

 through D5, have 

been identified.

Agonists are compounds not normally found in the body 

that stimulate receptors in the same way that neurotransmitters do. Consequently, D3

 agonists are compounds that 

stimulate D3

 receptors.

The PCP-Schizophrenia Connection

Dr. Jeffrey Witkin, Dr. Maciej Gasior, and their colleagues at NIDA’s Intramural Research Program 

in Baltimore, Neurogen Corporation in Branford, 

Connecticut, and the University of Groningen in the 

Netherlands have found that, in mice, a D3

 agonist 

called (+)-PD 128,907 can block psychotic-like behavior 

induced by a PCP derivative. Because research suggests 

that compounds that can reduce this type of psychotic 

behavior also will reduce symptoms of schizophrenia, Dr. 

Witkin’s team believes the agonist has potential to treat 

schizophrenia as well.

Developed as a general anesthetic in the late 1950s, PCP 

became widely abused as a hallucinogen starting in the 

late 1960s. PCP abusers began appearing at hospital emergency rooms exhibiting symptoms that were nearly indistinguishable from those of schizophrenia, including hallucinations, paranoia, emotional withdrawal, and loss of 

speech. This commonality of symptoms led researchers to 

suspect that whatever PCP was doing in the brain might 

also be happening in the brains of schizophrenics.

The Witkin group’s discovery of the potential of D3

 agonists for treating PCP psychosis and schizophrenia sprang 

from their exploration into another property of D3

 agonists that previous research had unveiled—their potential 

for reducing cocaine self-administration in rats, a finding 

that suggests they may reduce cocaine craving in humans. 

In the course of the researchers’ exploration of that property, they noticed that (+)-PD 128,907 produced an 

unusual sedative effect on the animals that was similar to 

that of clozapine, a medication commonly used for treating schizophrenia.

“Clozapine produces a very striking depressant action that 

can be distinguished from that of other types of depressant drugs,” explains Dr. Witkin. “Animals on clozapine 

are reactive to stimuli in the environment, and yet they 

Volume 14, Number 6 (March, 2000)

Potential Medications Mimic Brain Chemical

Compounds that show promise for treating psychosis and cocaineinduced seizures mimic the action of the messenger chemical dopamine on certain nerve cells in the brain. The compounds—called 

D3 agonists—stimulate molecules on nerve cells that receive dopamine messages—called dopamine D3

 receptors. Scientists have yet 

to learn how this action reduces psychotic symptoms and seizures.
113

are sedate. Also, their movements are normal. In contrast, 

other sedative-like compounds tend to make animals 

uncoordinated.”

Because the D3

 agonist acted like a medication for schizophrenia and because of the similarities between PCP psychosis and schizophrenia, the researchers decided to try 

the agonist in mice exhibiting psychotic-like symptoms 

as a result of being given a PCP derivative. Among those 

symptoms are headweaving, a popcorn-like jumping, and 

repetitive treading with a forepaw. The forepaw treading 

is easiest to measure.

Dr. Witkin and his colleagues found that (+)-PD 128,907 

reduced this forepaw treading as effectively as clozapine 

and more effectively than haloperidol, the most commonly used antipsychotic medication. The compound 

also caused no movement disorders. “This is good news 

because haloperidol treats only some schizophrenic symptoms and also causes severe movement disorders,” says Dr. 

Witkin. “Clozapine, on the other hand, is effective against 

all symptoms and generally does not cause movement 

disorders but can cause a life-threatening blood disorder. 

Altogether, these findings indicate that (+)-PD 128,907 

might be an effective alternative to clozapine and haloperidol for treating schizophrenia,” he says.

Blocking Cocaine-Induced Seizures and Deaths

Dr. Witkin and Dr. Gasior next tested the effectiveness 

of D3

 agonists against cocaine-induced seizures and deaths 

in mice. They pursued their new line of research on the 

basis of a NIDA-funded study at the University of Miami 

showing that the brain’s D3

 receptors might be involved in 

seizures and deaths among cocaine abusers.

Again, (+)-PD 128,907 proved effective, and so did the 

other D3

 agonists. Whether given before or after a cocaine 

overdose was administered, the compounds completely 

blocked the convulsant and lethal effects of the cocaine. 

“This is a dramatic finding because current medications 

do not work very well against the seizures and other 

consequences of cocaine overdoses,” says Dr. Witkin.

Why D3 agonists should reduce cocaine self-administration, 

psychotic-like behavior, and cocaine-induced seizures and 

death is not yet clear, says Dr. Witkin. “More often than 

not in medications development, researchers find an 

interesting effect of a compound through trial and error, 

and then they try to figure out why the compound has 

that effect,” he says. “That’s where we are now with the 

D3

 agonists.”

Sources

• Staley, J.K., and Mash, D.C. Adaptive increase in 

D3 dopamine receptors in the brain reward circuits 

of human cocaine fatalities. Journal of Neuroscience 

16(19):6100–6106, 1996.

• Witkin, J.M., and Gasior, M. Dopamine D3

receptor involvement in the convulsant and lethal 

effects of cocaine. Polish Journal of Pharmacology

50(suppl.): 44–45, 1998.

• Witkin, J.M., et al. Atypical antipsychotic-like 

effects of the dopamine D3

 receptor agonist, 

(+)-PD 128,907. European Journal of Pharmacology

347:R1–R3, 1998. 
114

Research Findings

Combining Drug Counseling Methods Proves Effective in Treating 

Cocaine Addiction

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 14, Number 5 (December, 1999)

NIDA’s research into treatments for cocaine abuse has 

identified a variety of effective treatments ranging from 

group drug counseling to individualized psychotherapies. 

In a NIDA-funded clinical trial investigating the efficacy 

of four types of treatment, patients who received group 

drug counseling combined with individual drug counseling were more likely to reduce their drug use than were 

patients who received group drug counseling alone or in 

combination with psychotherapies that are used to treat 

addictions.

The NIDA Collaborative Cocaine Treatment Study 

involved 487 patients with relatively low levels of psychiatric severity whose principal diagnosis was cocaine dependence as defined by the Diagnostic and Statistical Manual 

of Mental Disorders. The drug counseling therapies evaluated in the multisite study are specifically designed to 

treat drug use; the psychotherapies—supportive-expressive 

therapy and cognitive therapy—are 

less focused on drug use. 

The study involved patients recruited 

at five sites—the University of 

Pennsylvania in Philadelphia; 

the Western Psychiatric Institute 

and Clinic at the University of 

Pittsburgh; Massachusetts General 

Hospital in Boston; McLean 

Hospital in Belmont, Massachusetts; 

and Brookside Hospital in Nashua, 

New Hampshire. Each research center provided four treatments: group 

drug counseling alone, group drug counseling combined 

with individual drug counseling, group drug counseling 

combined with cognitive therapy, or group drug counseling 

combined with supportive-expressive therapy. Each of the 

487 patients was randomly assigned to one of the therapies. Treatment results were evaluated through patient 

self-reporting, weekly observed urine testing, and the 

Addiction Severity Index—an interview-based assessment 

used to measure treatment outcome. 

During each of the 6 months of treatment, and at 3 

months and 6 months after treatment ended, patients who 

received combined individual and group drug counseling 

used less cocaine and drugs overall than did patients who 

received other forms of treatment. A higher percentage of 

combined drug counseling patients were able to achieve 

abstinences of 1, 2, and 3 months than were patients in 

the other study groups. During the 6 months after treatment 

ended, 38 percent of patients who completed combined 

counseling treatment maintained drug-free periods of 3 

consecutive months compared with 27 percent of patients 

treated with group counseling alone, 23 percent of patients 

treated with cognitive therapy plus group counseling, and 

18 percent of patients receiving supportive-expressive therapy 

plus group counseling. In addition, patients who received 

combined drug counseling showed more improvement 

in Addiction Severity Index ratings than did patients 

receiving other treatments. “These results underline the 

valuable role of well-designed drug counseling in treating 

drug abuse. More specifically, this study demonstrates the 

effectiveness that combined counseling 

therapies can have in treating cocaine 

addiction,” notes Dr. Jack Blaine 

of NIDA’s Division of Treatment 

Research and Development. 

“The success of combined drug counseling treatment compared with the 

psychotherapies may be due to the 

fact that drug counseling delivers a 

message that is simple and strong—

stay away from the situations where 

you use drugs and the people you use 

drugs with. The counselors at all sites 

involved in our study were able to deliver that message 

effectively,” says Dr. Paul Crits-Christoph of the University 

of Pennsylvania, who coordinated the multicenter study. 

Criteria for Success

“The success of combined drug counseling compared 

with other treatments is the result of the nature, intensity, and quality of counseling,” Dr. Crits-Christoph says. 

“We paid a great deal of attention to selecting and training 

counselors, all of whom had extensive previous experience 

treating patients with substance abuse disorders.” The 

counselors and psychotherapists received more than a year 

of training in standardized therapy using published manuPatients who received 

combined individual and 

group drug counseling 

used less cocaine than 

did patients who received 

other forms of treatment.
115

als, and were evaluated during training and certified prior 

to participation in the collaborative treatment study. 

Group drug counseling, given to all study participants, 

consisted of weekly sessions for the full 6 months of the 

study and individual meetings with the group counselor 

once per month during a 3-month “booster” phase following the 6 months of active treatment. Patients in 

individual drug counseling and psychotherapy treatments 

participated in twice-weekly sessions during the first 3 

months, weekly sessions during the second 3 months, and 

monthly meetings during the booster phase. 

Group drug counseling treatment involved an initial 

3-month phase during which patients were educated 

about the concepts in recovery from addiction, and a second 3-month phase that involved open group discussions 

focusing on patients helping each other solve problems 

encountered in recovery. Individual drug counseling 

focused on helping patients achieve and maintain abstinence through behavioral changes such as avoiding situations that trigger drug use. Group drug counseling and 

individual drug counseling encouraged patient involvement in self-help and support groups such as Cocaine 

Anonymous outside of scheduled treatment sessions. 

Cognitive therapy involved identifying the underlying 

beliefs related to a patient’s drug use. Therapists worked 

with patients to evaluate the advantages and disadvantages 

of their beliefs. They also employed role-playing, behavioral experiments, and scheduling and monitoring activities. Supportive-expressive therapy involved identifying 

interpersonal conflicts that relate to a patient’s drug use. 

Therapists helped patients interpret the role that these 

conflicts play in drug use and problems encountered in 

stopping drug use. 

Because treatment and training were based on published 

manuals, it may be possible for other treatment programs 

to achieve similar results, Dr. Crits-Christoph notes. “If 

other programs can apply these tools with the intensity 

that characterized this study, their outcomes should be 

similarly successful.” 

Sources

• Crits-Christoph, P., et al. The National Institute on 

Drug Abuse collaborative cocaine treatment study: 

Rationale and methods. Archives of General Psychiatry

54(8):721–726, 1997. 

• Crits-Christoph, P., et al. Psychosocial treatments for 

cocaine dependence: Results of the National Institute 

on Drug Abuse collaborative cocaine treatment study. 

Archives of General Psychiatry 56(6):493–502, 1999. 

• Crits-Christoph, P., et al. Training in cognitive, supportive-expressive, and drug counseling therapies for 

cocaine dependence. Journal of Consulting and

Clinical Psychology 66(3):484–492, 1998. 
Research Findings

116

Research Shows Effects of Prenatal Cocaine Exposure Are Subtle 

But Significant

By NIDA Director Dr. Alan I. Leshner 

Volume 14, Number 3 (September, 1999)

There is a traditional belief in the Aymara 

community of Peru and Bolivia that if a 

woman sees a corpse during pregnancy, her 

baby is likely to be sickly. The scientific 

understanding of prenatal exposures to toxic 

substances is more complicated. Depending 

on the specific substance and dose and the 

particular organ systems that are developing at the time of the exposure, impacts 

may vary greatly in type and severity. While 

exposure to alcohol has a devastating impact 

on some children, exposures to cocaine and 

other illicit drugs seem to produce much 

more subtle effects. 

In the 1980s, observers reported a variety of 

possible abnormalities among some infants 

of mothers who used crack cocaine during 

pregnancy. Among them were lethargy and 

nonresponsiveness, frenetic movements, low 

pain thresholds, problems relating to caregivers, and absence of normal playfulness. 

These anecdotal reports amplified the existing 

alarm over an epidemic of drug use that had 

already produced extraordinary accounts of 

violence and familial dysfunction. Scientific 

research was needed to determine which of 

the suspected abnormalities were real, which 

were actually due to cocaine exposure, and 

what was portended for these children’s 

future. 

Since the beginning of the crack epidemic, 

NIDA-supported researchers have been 

following two important lines of investigation into the effects of prenatal exposure to 

cocaine. Basic researchers have been looking at cocaine’s impact on fetal development in laboratory animals. At the same time, clinical researchers have 

been conducting longitudinal studies to track groups of 

cocaine-exposed babies in order to determine how prenatal exposure would influence their development from birth 

through adolescence. 

To date, NIDA’s longitudinal studies have confirmed that 

some children with prenatal cocaine exposure have 

problems with aspects of motor skills, IQ, fussiness and 

consolability, and attention span. Executive 

function—the ability to gather and use 

information in pursuit of one’s own aims—

also may be compromised. In general, these 

findings are consistent with results from 

studies with laboratory animals, which have 

shown that cocaine alters the development 

of neural systems that are crucial to behavior 

and response to stimuli. 

There are three important points to make 

about what we have learned so far. First, 

worries that “crack babies” would never be 

able to function in society have turned out 

to be unfounded for the great majority of 

these children. Despite the documented deficits of some of the children in our longitudinal studies, most have passed one developmental milestone after another, albeit some 

more slowly than their unexposed peers. 

Researchers have had the gratifying experience of watching many of these children 

grow, walk, talk, interact with their families 

and social environments, and progress from 

grade to grade in school. 

Second, even though our worst fears about 

prenatal cocaine exposure have not been 

realized, we should not be complacent. 

While studies have clearly established that 

such exposure damages few children beyond 

any hope of help, they have also shown that 

some children are affected in ways that put 

them in need of special help. Even when 

deficits are relatively slight, their potential 

negative consequences can be important over 

the long term. A child with slightly more 

difficulty in settling down to tasks, for example, may do 

poorly in school. A child who has minor difficulties in 

controlling emotions may develop significant family and 

social problems over time, especially in environments that 

feature drug abuse and its associated ills. 

Brain function deficits that are slight on an individual 

basis also can have sizable impacts on society. For example, a recent analysis by researchers at Brown University 

in Providence, Rhode Island, of data from several studies 

The ultimate 

objective of 

NIDA’s research 

program is 

to be able to 

design and 

provide effective 

assistance to 

children who 

need to 

overcome 

difficulties 

resulting from 

fetal cocaine 

exposure. 
117

concluded that children with fetal cocaine exposure have 

IQs that average 3.3 points lower than those of unexposed 

children from the same socioeconomic environments. 

For most children, a difference of such magnitude would 

not matter much in terms of school performance or life 

prospects. For some children, however, 3.3 IQ points 

can spell the difference between functioning in the regular classroom and needing specialized help. The Brown 

researchers estimated that lower IQs associated with fetal 

cocaine exposure increase the number of children in the 

Nation who need special educational services 

by as many as 80,550 per year. The cost of 

providing these services could be as high as 

$352 million each year. 

Finally, some children who have avoided 

major problems so far may still hit snags in 

the future. The oldest children in the longitudinal studies are approaching adolescence. 

Will fetal cocaine exposure produce heightened vulnerability to subsequent drug abuse 

and addiction during this often-difficult 

developmental stage? Some evidence from 

animal studies suggests that it may. Given 

an unrestricted supply of cocaine, the offspring of mice injected with cocaine during 

pregnancy self-administer more of the drug than do other 

mice. Also suggestive is a recent finding by NIDA-funded 

researchers that the fetal mouse brain has active dopamine 

receptors. The researchers speculate that cocaine stimulation during gestation could enhance the proliferation of 

these receptors during human fetal development. If so, the 

resulting extra abundance of receptors might predispose 

the individual to react strongly to addictive drugs. 

We still have much to learn about cocaine’s impact on the 

developing human brain. Not only are the brain alterations associated with fetal cocaine exposure various and 

often subtle, they also may manifest themselves in different ways as children grow. Moreover, the environments 

associated with prenatal cocaine exposure almost always 

contain other potential stumbling blocks for child development. These can range from poor maternal nutrition 

during pregnancy and prenatal or postnatal exposures to 

other drugs to parental neglect or abuse and elevated risks 

for a variety of other illnesses. 

To isolate the specific effects of cocaine exposure from 

all of these confounding factors is a daunting challenge, 

but NIDA-supported researchers have 

made impressive strides in developing 

research protocols, interview techniques, 

and evaluation tools that help discriminate cocaine’s effects. NIDA continues to 

strongly encourage researchers to explore 

ways to further develop these resources. As 

this research bears fruit, and even better 

tools—such as improved brain imaging, 

reliable biologic measures of cocaine exposure, and innovative instruments for cognitive assessment—become available, our 

understanding of the impact of prenatal 

cocaine exposure will grow. 

The NIDA NOTES article “NIDA Studies 

Clarify Developmental Effects of Prenatal Cocaine 

Exposure” reports on some of the latest studies that are 

isolating the impacts of prenatal cocaine exposure from 

those of the environment. 

The ultimate objective of NIDA’s research program, of 

course, is to be able to design and provide effective assistance to children who need to overcome difficulties resulting from fetal cocaine exposure. In fact, there is good reason to hope that the insights into human development 

gained from these studies also will benefit children who 

were never exposed to drugs. 

Even though our 

worst fears about 

prenatal cocaine 

exposure have not 

been realized, we 

should not be 

complacent.
Research Findings

118

NIDA Studies Clarify Developmental Effects of Prenatal 

Cocaine Exposure

By Patrick Zickler, NIDA NOTES Staff Writer

NIDA-funded studies have demonstrated that cocaine can 

reach into the womb and disrupt the embryonic development of crucial neurological systems in animals, but the 

effects of prenatal cocaine exposure on human development are far more difficult to assess. Mothers who use 

cocaine may use other drugs, and factors such as prenatal 

care, nutrition, and home environment contribute to a 

child’s development before and after birth. Thus, isolating 

the impact of prenatal cocaine exposure is difficult, but 

NIDA-supported research has begun to provide a clearer 

picture of the damage prenatal cocaine exposure causes. 

“We now have data from longitudinal studies that have 

followed mothers from early in their pregnancies and 

their children from birth into early childhood,” says Dr. 

Vincent Smeriglio of NIDA’s Center on AIDS and Other 

Medical Consequences of Drug Abuse. “These studies take into account many confounding factors that are 

associated with cocaine use. What we see in some of these 

children is a pattern of subtle neurobehavioral effects 

associated with prenatal cocaine exposure. These include 

effects on a child’s attention and alertness, IQ, and motor 

skills. The effects are not as profound as some early 

reports suggested, but they are very real,” he says.

Effects on Attention, Alertness, and Intelligence

Studies with laboratory animals have revealed cocainerelated effects on development within regions of the brain 

that regulate attention, arousal, and reaction to stresses. 

Research involving children born to mothers who used 

cocaine during pregnancy has found a profile of effects 

related to these same brain regions. The effects are not 

dramatic—cocaine-exposed children were more likely than 

unexposed children to have scores at the low end of the 

normal ranges on tests that measure alertness, attention, 

and intelligence. However, the effects persist from birth 

through early childhood and suggest that cocaine-exposed 

children may have to work harder—or will need more 

help—focusing their attention, remaining alert, and processing information than do unexposed children.

NIDA-supported research conducted by Dr. Linda Mayes 

at the Yale University School of Medicine in New Haven, 

Connecticut, suggests that cocaine has an effect on regions 

of the brain that regulate a child’s ability to pay attention, 

which has important implications for learning and memory. 

Dr. Mayes and her colleagues studied more than 600 

children—either not exposed to any drug or exposed 

prenatally to cocaine; to cocaine and marijuana, tobacco, 

or alcohol; or to marijuana, tobacco, or alcohol but not to 

cocaine. The children were examined at ages 3, 12, 18, and 

24 months. “In a variety of settings, cocaine-exposed children 

appear to require more stimulation to increase arousal and 

attention but are less able to control higher states of arousal 

than are unexposed children,” Dr. Mayes says.

NIDA-funded research conducted at the University 

of Florida in Gainesville has demonstrated an association between the amount of cocaine used by a pregnant 

mother and her child’s performance on tests used to measure alertness and attention. Dr. Fonda Davis Eyler and 

Dr. Marylou Behnke studied more than 300 infants, half 

whose mothers used cocaine during pregnancy and half 

whose mothers did not. “The amount of cocaine used 

during pregnancy was negatively related to the baby’s 

Dr. Marylou Behnke (left) and Dr. Fonda Davis Eyler have found

that babies exposed prenatally to cocaine are less alert and attentive 

than are unexposed infants.

Volume 14, Number 3 (September, 1999)
119

scores on tests of orientation, attention, and alert responsiveness,” says Dr. Eyler.

Unlike many other studies that have examined the effects 

of prenatal cocaine exposure, the research conducted by 

Dr. Eyler and Dr. Behnke involved women from poor 

rural populations rather than women from urban areas 

where cocaine abuse often is accompanied by abuse of a 

variety of other drugs. “Cocaine is pervasive in this community, but other illicit drugs—except marijuana—are 

not. This makes it easier for us to isolate the effects of 

cocaine,” Dr. Behnke notes.

Although the researchers caution that it is impossible to 

attribute the observed effects solely to cocaine use, they 

note that the number of significant correlations with 

cocaine are far greater than would be expected by chance. 

“The results seem to fit into an overall pattern of effects. 

Twice as many cocaine-exposed infants as controls—a 

fourth of the sample—were unable to achieve and maintain the quiet alert state that examiners need to administer 

some parts of the test,” observes Dr. Eyler. “In simple 

comparisons as well as in more complex correlations with 

amount of usage, it was the cocaine-exposed infants who 

demonstrated significant detriments, and it was always in 

the areas of responsiveness and regulation of attention,” 

she says.

At the Western Psychiatric Institute and Clinic in 

Pittsburgh, NIDA-funded researcher Dr. Gale Richardson 

and her colleagues also have found an association between 

prenatal cocaine exposure and central nervous system 

deficits. “Cocaine has effects that are independent of other 

prenatal and postnatal factors. This has been true at each 

of the three age phases in our study—at birth, at age 1, 

and at age 3, the neurobehavioral effects are there,” Dr. 

Richardson says.

At birth, the children exposed prenatally to cocaine 

showed more abnormal reflexes, less motor maturity, and 

poorer ability to regulate their state of attentiveness than 

did unexposed children. At 1 year and at 3 years, those 

children were less adaptable and more likely to be fussy 

and overly persistent than were unexposed children.

At 3 years, the exposed children scored lower on an 

intelligence test than did unexposed children, were more 

restless, had shorter attention spans and less focused 

attention, and made more attempts to distract the examiner 

than did children who were not exposed to cocaine before 

birth, Dr. Richardson notes.

The study will follow children through 10 years of age 

and will allow researchers to control for many of the 

circumstances, such as multiple drug exposure and preand postnatal environment, that might mask or confound 

cocaine-related effects. “We have a large sample of women 

who were enrolled early in their pregnancies from a prenatal care clinic, not a drug treatment program. We have 

continued to interview the mothers extensively to collect 

as much information as possible about the postnatal 

environment,” Dr. Richardson says.

Effects on Motor Development

NIDA-funded research conducted by Dr. Robert Arendt 

and Dr. Lynn Singer at Case Western Reserve University 

in Cleveland has shown an association between prenatal cocaine exposure and decreased motor development 

in children at age 2. Their study involved nearly 200 

cocaine-exposed and unexposed infants recruited from an 

urban hospital newborn nursery and pediatric 

clinic.

“The cocaineexposed children 

performed significantly less well on 

both the fine and 

the gross motor 

development indices. These findings indicate that 

the lag in development extends 

beyond the neonatal 

period in exposed 

children,” Dr. 

Arendt says.

“Motor functions are more 

‘hard-wired’ than 

behavior, and 

are less likely to 

be influenced 

by environment 

as a child grows 

up. The effects 

of cocaine exposure on motor 

development that 

show up early 

should still be there as the child grows older,” Dr. Singer 

says. “We previously found motor development effects in 

the cocaine-exposed group when we looked at them at 4 

months and again at 12 months. Now we know that these 

effects persist through age 2,” she adds.

Preliminary data from examination of the same children 

at age 4 suggest that cocaine-related deficits in fine motor 

development last into early childhood, although the motor 

skill problems associated with prenatal cocaine exposure 

are not more severe than those seen in some unexposed 

children in the course of normal clinical practice, Dr. 

Arendt notes. “These kids can be helped with physical 

During their first few years of life, children 

develop the fine motor skills that help them 

learn to write and draw. NIDA-supported 

research suggests that prenatal exposure to 

cocaine has a damaging effect on the development of these skills and on a child’s ability 

to remain alert and attentive.
120

therapy and other interventions just as successfully as any 

other child with similar motor problems. It’s important to 

know that they will need some help, and it’s important to 

see to it that they get this help. Without properly developed motor skills, it is difficult for a child to control a 

pencil to draw a picture or write their ABCs,” Dr. Arendt 

says.

“No study involving mothers and children in an environment of drug abuse can perfectly isolate the effects of 

cocaine or any other drug from the combined effects of 

that environment, but we can use statistical methods and 

study design to control for many of the confounding variables. What we see is that cocaine does have an effect that 

is independent of other variables,” Dr. Arendt says.

Sources 

• Arendt, R.; Angelopoulos, J.; Salvator, A.; and Singer, 

L. Motor development of cocaine-exposed children at 

age two years. Pediatrics 103:86–92, 1999.

• Arendt, R., et al. Sensorimotor development in 

cocaine-exposed infants. Infant Behavior and 

Development 21:627–640, 1998.

• Eyler, F.D.; Behnke, M.; Conlon, M.; Woos, N.S.; 

and Wobie, K. Birth outcome from a prospective, 

matched study of prenatal crack/cocaine use; II. 

Interactive and dose effects on neurobehavioral assessment. Pediatrics 101:237–241, 1998.

• Mayes, L.; Grillon, C.; Granger, R.; and Schottenfeld, 

R. Regulation of arousal and attention in preschool 

children exposed to cocaine prenatally. Annals of the 

New York Academy of Sciences 846:126–143, 1998.

• Richardson, G.A. Prenatal cocaine exposure: A longitudinal study of development. Annals of the New York 

Academy of Sciences 846:144–152, 1998.

• Smeriglio, V.L., and Wilcox, H.C. Prenatal drug 

exposure and child outcome. Clinics in Perinatology

26(1):1–16, 1999. 
Research Findings

121

Cocaine’s Pleasurable Effects May Involve Multiple Chemical Sites 

In the Brain

By Steven Stocker, NIDA NOTES Contributing Writer

Recent studies with genetically altered mice have suggested that cocaine’s euphoric effects may involve not just 

one, but several, chemical sites in the brain. These studies 

indicate that medications for treating cocaine addiction 

may need to target these multiple sites just as cocaine 

does. 

Scientists have known for many years that cocaine blocks 

the reuptake of certain chemicals by nerve cells, or neurons, 

in the brain. Neurons release these chemicals, called 

neurotransmitters, to send messages to other neurons in 

the vicinity. Once communication has taken place, the 

neurons that sent the neurotransmitters recycle them for 

further use. Proteins called transporters, located on the 

surface of the sending neurons, latch onto the neurotransmitters outside the neurons in the extracellular space and 

transport them back inside for re-release at a later time.

Early studies showed that cocaine blocks the transporters 

for three different neurotransmitters: dopamine, serotonin, 

and norepinephrine. Later, one vein of research suggested 

that cocaine’s blockade of the dopamine transporter was 

most important for producing the drug’s euphoric effects. 

By blocking the dopamine transporter, some scientists 

theorized, cocaine might raise the level of extracellular 

dopamine in brain regions involved in the feeling of pleasure. 

This excess dopamine could continue to affect neurons in 

these regions, giving rise to euphoria.

If this hypothesis is true, then eliminating the dopamine 

transporter in the brain should eliminate cocaine’s euphoric 

effects. To test the hypothesis, scientists produced mice 

lacking dopamine transporters by inactivating or “knocking out” the gene for the transporter in mouse embryos. 

When these dopamine transporter “knockout” mice 

matured, the researchers studied whether they found 

cocaine to be rewarding. Researchers used two techniques 

to study whether elimination of the dopamine transporter 

nullified cocaine’s rewarding effects.

Dr. Beatriz Rocha, then at the University of North Texas 

Health Science Center in Fort Worth and now in NIDA’s 

Intramural Research Program (IRP) in Baltimore, and 

Dr. Marc Caron’s group at Duke University in Durham, 

North Carolina, used a procedure in which the mice 

pressed a lever to receive a cocaine injection. If the mice 

continually pressed the lever at a high rate, this would 

indicate that they found cocaine rewarding.

Dr. Ichiro Sora, Dr. George Uhl, and their colleagues in 

NIDA’s IRP, the IRP of the National Institute of Mental 

Health in Bethesda, Maryland, and the University of 

WŸrzburg in Germany used a different procedure called 

conditioned place preference. In this procedure, mice 

were given cocaine injections when they were in one comVolume 14, Number 2 (August, 1999)

During normal communication between nerve cells, or neurons, 

the transmitting neuron releases neurotransmitter molecules that 

stimulate the receiving neuron by binding to receptor molecules 

on its surface. After this communication has occurred, transporter 

molecules collect the released neurotransmitters and transport them 

back into the transmitting neuron for later release. When cocaine is 

present, the drug blocks the transporter, preventing neurotransmitter reuptake so that the neurotransmitters continue to stimulate the 

receiving neuron.
122

partment of a two-compartment chamber and were given 

nothing when they were in the other compartment. Later, 

the researchers would observe which compartment the 

mice moved to when they were given a choice. If the mice 

found cocaine rewarding, they would spend more time 

in the compartment where they had received the cocaine 

injections.

Using the different procedures, both groups found that 

their knockout mice found cocaine rewarding despite not 

having the dopamine transporter. The mice either selfadministered cocaine or chose the side of the cage where 

they had received cocaine.

“This finding surprised us at first,” says Dr. Uhl. “It 

shows that the dopamine transporter is not necessary for 

cocaine reward.” Dr. Rocha says that she, too, was surprised by her findings, but the fact that she and her colleagues and Dr. Uhl’s group had complementary results 

adds weight to the findings.

If the dopamine transporter is not the crucial site for producing cocaine reward, then what is? Apparently not the 

serotonin transporter, because Dr. Uhl’s group also studied serotonin transporter knockout mice and found that 

these mice also found cocaine rewarding.

Dr. Uhl and Dr. Rocha speculate that perhaps cocaine 

produces its rewarding effects by blocking the dopamine 

transporter and the serotonin transporter at the same time. 

Thus, the elevation in the levels of both dopamine and 

serotonin might produce the feelings of pleasure.

In Dr. Rocha’s study, the researchers found that the 

extracellular dopamine level in a key brain region in the 

dopamine transporter knockout mice was nearly five 

times higher than normal because the transporters were 

no longer there to shuttle the dopamine molecules back 

inside the neurons. When the knockout mice were given 

cocaine, the extracellular dopamine level did not go any 

higher because the animals had no dopamine transporters 

for cocaine to block. Although the researchers have yet to 

measure the extracellular serotonin levels in these knockouts, Dr. Rocha figures that the levels increased and then 

decreased as other studies have shown they do in normal 

mice because knocking out the dopamine transporter 

probably would not affect cocaine’s blockade of the serotonin transporter. 

The increase in serotonin, combined with the already high 

level of dopamine, may be why cocaine is rewarding for 

the dopamine transporter knockout mice, according to 

Dr. Rocha.

Dr. Uhl also believes that more than one neurotransmitter in the brain probably mediates cocaine reward, if only 

because more than one neurotransmitter probably mediates pleasure in general. “If a species is not rewarded by 

activities such as eating or sexual interactions, that species is not going to survive,” he says. “So it makes sense 

that the brain would have redundant systems so that if 

a mutation or some other factor disrupts one system, 

the other systems can still operate normally to produce 

reward.” Different neurotransmitters might mediate different aspects of reward, he says. The explanation for 

The explanation for cocaine’s 

powerful attraction may be that it 

affects several neurotransmitters, 

all of which are involved in 

mediating pleasure.

In normal mice, researchers have found that cocaine raises the levels 

of dopamine and serotonin outside neurons about 150 percent,

but the levels return to normal after about 2 hours. In Dr. Rocha’s 

study, the researchers found that the dopamine levels in dopamine 

transporter knockout mice were about 500 percent higher than

normal because no transporters were available to shuttle the dopamine molecules back inside the neurons. 

Although the researchers have yet to measure the extracellular serotonin levels in these knockouts, Dr. Rocha theorizes that the levels 

increase then decrease as in normal mice because knocking out the 

dopamine transporter probably would not affect cocaine’s blockade 

of the serotonin transporter.

Effects of Cocaine on Neurotransmitter Levels
123

cocaine’s powerful attraction may be that it affects several 

neurotransmitters, all of which are involved in mediating 

pleasure.

Selective or Nonselective?

Both Dr. Uhl and Dr. Rocha think that the results of their 

dopamine transporter knockout studies support the idea 

that medications for treating cocaine addiction should target 

other neurotransmitters in addition to dopamine. Dr. David 

McCann, chief of NIDA’s Pharmacology and Toxicology 

Branch, notes that starting in the early 1990s NIDA, in 

collaboration with pharmaceutical firms, began developing 

a number of potential cocaine treatment medications that 

prevent cocaine from acting at neurotransmitter transporters. Some of these compounds are selective for the dopamine 

transporter, while others act more or less equally at dopamine, serotonin, and norepinephrine transporters.

A compound that is selective for the dopamine transporter 

is GBR12909. A compound that blocks all three transporters about equally is NS2359, which was developed by 

NIDA and NeuroSearch, a Danish pharmaceutical firm. 

Animal studies with these compounds have indicated that 

they are safe and potentially effective in humans, and they 

are now in the early phases of human clinical trials.

Sources

• Rocha, B.A.; Fumagalli, F.; Gainetdinov, R.R.; 

Jones, S.R.; Ator, R.; Giros, B.; Miller, G.W.; 

and Caron, M.G. Cocaine self-administration 

in dopamine-transporter knockout mice. Nature 

Neuroscience 1(2):132–137, 1998.

• Sora, I.; Wichems, C.; Takahashi, N.; Li, X-F; Zeng, 

Z.; Revay, R.; Lesch, K-P; Murphy, D.L.; and Uhl, 

G.R. Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proceedings of the 

National Academy of Sciences USA 95(13):7699–7704, 

1998. 
Research Findings

124

Blood-borne Medications Could Intercept Drugs Before 

They Reach the Brain

By Patrick Zickler, NIDA NOTES Staff Writer 

The damage done by cocaine and other drugs of abuse 

takes place among neurons deep in the brain, but the drugs 

are transported to these nerve cells by the blood. A number 

of researchers are investigating possible medications that 

could intercept and neutralize cocaine and other drugs in 

the bloodstream, preventing them from initiating the 

neurochemical reactions that lead to abuse and addiction. 

“This represents a different approach to therapeutic 

research, which has most often focused on interfering 

with a drug’s activity in the brain. This strategy is aimed 

at preventing the drug from reaching the brain,” says Dr. 

Steven Sparenborg of NIDA’s Medications Development 

Division. 

Blood-borne medications, referred to as peripheral blockers, would offer several advantages over other pharmacological approaches to addictions, notes Dr. David Gorelick 

of NIDA’s Intramural Research Program. They do not 

require knowledge of how or where the abused drug acts 

in the brain, they would be effective against drugs with 

multiple sites of action in the brain, and they could 

protect against a drug’s actions—such as cardiovascular 

toxicity—at sites outside the central nervous system. 

Peripheral blockers are modeled after the enzymes and 

antibodies of the body’s natural defense system, according to Dr. Sparenborg. One peripheral blocker approach 

would bind drugs like cocaine, phencyclidine (PCP), or 

nicotine to antibodies, creating a drug-antibody complex 

that is too large to move through blood vessel walls into 

the brain. This would trap the drug within the bloodstream until it could be eliminated from the body through 

normal kidney activity. Another approach would enhance 

the rate at which naturally occurring enzymes break down 

drug molecules into inactive byproducts. A third method 

under investigation employs an engineered antibody that 

both binds to and breaks down drugs. Although individuals 

might overcome the action of these peripheral blockades 

by taking more of the drug and overwhelming the antibody 

or enzyme, effective blood-borne medications would serve 

as valuable components of treatment programs that protect 

against relapse or counteract acute toxic effects from drugs 

of abuse. 

“There is still a long way to go with this research, but the 

validity of the approach has been demonstrated in animal 

tests. First-phase clinical trials of an active cocaine vaccine 

are under way now, and we’re encouraged by the progress,” says Dr. Sparenborg. 

Immunization

Molecules as small as cocaine typically do not trigger the 

body’s immune system to create antibodies. However, 

Dr. Barbara Fox and her colleagues at ImmuLogic 

Pharmaceutical Corporation in Waltham, Massachusetts, 

have developed a technique that links cocaine derivatives 

to a larger protein molecule, or carrier, to stimulate an 

immune reaction. Animals vaccinated with the cocainecarrier combination develop cocaine-specific antibodies 

that bind with cocaine in the blood, preventing most of 

the drug from reaching the brain. 

“In mice, the vaccine induced an antibody response that 

kept cocaine from reaching its targets in the central nervous 

system,” says Dr. Fox, now with Addiction Therapies, 

Inc., in Wayland, Massachusetts. “And it appears to be 

long-lasting. Periodic boosters maintained the response 

for more than a year, which is a significant portion of a 

mouse’s life.” 

The vaccine, which is currently being studied in 

first-phase human trials by researchers with Cantab 

Pharmaceuticals, uses a protein that generates a strong 

antibody response as a carrier. More than two dozen 

fragments of the cocaine molecule are bound to the carrier. 

When injected into animals, the large protein molecules 

stimulate the production of antibodies that recognize the 

cocaine fragments. Moreover, the antibodies also bind to 

norcocaine, one of cocaine’s minor but pharmacologically 

active metabolites, or byproducts, but do not bind to the 

Volume 14, Number 2 (August, 1999)

These results suggest that catalytic 

antibodies have the unique potential both to treat the acute effects of 

cocaine overdose and to block 

some of the chronic reinforcing 

effects of abuse.
125

more abundant but inactive ones. “This means that the 

antibodies don’t become saturated with inactive metabolites 

and lose the capacity to bind with cocaine,” Dr. Fox says. 

Dr. Fox and her colleagues found that injecting cocaine 

into rats immunized with the compound resulted in significantly higher levels of cocaine in the blood, and correspondingly lower levels in the brain, than did injecting 

the same amount of cocaine into nonimmunized animals. 

As much as 63 percent of administered cocaine was bound 

in the blood as soon as 30 seconds after administration. 

In addition, immunized rats were much less likely to selfadminister cocaine than were nonimmunized rats. This 

finding, Dr. Fox notes, suggests that the vaccine could 

help prevent relapse in patients in drug treatment programs. “This is not a ‘magic bullet’ treatment. Patients 

could overcome it by taking more drug. But for motivated 

patients it could be a very valuable part of a comprehensive treatment program,” Dr. Fox says. 

Enzymes

Naturally occurring enzymes can break down cocaine 

and other drugs before they reach the brain, but they 

cannot rapidly neutralize the amounts of drugs that are 

typically ingested by drug abuse patients. Studies involving cocaine abusers suffering acute toxic reactions show a 

significant relationship between activity levels in the blood 

of butyrylcholinesterase (BChE), an enzyme produced in 

the liver, and the severity of cocaine toxicity. Patients with 

severe reactions to cocaine tend to have lower levels of 

BChE. NIDA-supported research has demonstrated that 

enhancing BChE activity can lead to improved treatment 

of cocaine overdose. 

Gilberto Carmona, a doctoral student in NIDA’s 

Intramural Research Program, has shown that the metabolism of cocaine in the blood can be dramatically increased 

and the drug’s effects decreased by raising BChE activity. Mr. Carmona and his colleagues demonstrated that 

cocaine half-life—the time needed for half the drug to be 

cleared from the blood—dropped from more than 5 hours 

to less than 5 minutes in rats pretreated with purified 

BChE that raised the enzyme’s blood activity 400-fold. 

The increase in BChE activity significantly decreased the 

increased motor activity caused by a cocaine injection and 

changed the pattern of cocaine metabolism, resulting in 

production of predominantly nontoxic byproducts rather 

than pharmacologically active ones. 

NIDA-supported researcher Dr. Oksana Lockridge at the 

University of Nebraska in Omaha has found that naturally-occurring variations in human BChE have different 

capacities for cocaine metabolism. “People who don’t 

have the typical variant may react to a ‘standard’ dose of 

cocaine as though it were an overdose,” Dr. Lockridge 

says. “Other variants exist at levels as low as one-third of 

normal levels, and people with these variants are probably 

at very high risk for cocaine toxicity.” 

Building on this knowledge of BChE variants, Dr. 

Lockridge and her colleagues engineered a mutant form of 

BChE— designated A328Y—that demonstrated four times 

the catalytic activity of normal BChE when tested in the 

laboratory. Dr. Kenneth Dretchen at Georgetown 

University in Washington, D.C., is conducting animal 

trials of A328Y to determine if the more active variant can 

be used as a treatment for cocaine overdose. “We know 

that the butyrylcholinesterase can reduce cocaine-induced 

convulsions, hyperactivity, and hypertension, and we 

know that A328Y will act much more aggressively to break 

cocaine down into inactive metabolites. A328Y could 

prove to be a valuable ‘crash cart’ tool for treating acute 

cocaine toxicity in emergency room situations,” he says. 

Catalytic Antibodies

Dr. Donald Landry, a researcher at Columbia University 

College of Physicians and Surgeons in New York City, 

has developed a cocaine-specific catalytic antibody—a 

compound that combines features of antibodies that bind 

to cocaine molecules with features of enzymes that break 

the drug down into inactive fragments. 

The catalytic antibody developed by Dr. Landry and his 

colleagues uses a molecule that mimics the structure of 

a cocaine molecule in its transition state—the shape of a 

cocaine molecule undergoing a chemical reaction. When 

the catalytic antibody binds to cocaine, the drug molecule 

takes on the configuration of the transition state. “This 

accelerates the rate of cocaine hydrolysis to inactive fragments. The antibody then releases the fragments and 

is free to bind to another cocaine molecule and initiate 

another cycle,” Dr. Landry explains. 

“Each molecule of the most potent antibody we have 

developed breaks down more than 2 cocaine molecules 

per minute and retains more than 95 percent of its activity through at least 200 turnovers,” Dr. Landry says. 

Animal tests of the antibody—designated mAB 15A10— 

demonstrate that it can reduce the toxic effects of cocaine 

overdose. Other tests show that pretreatment with the 

compound will prevent rats from self-administering 

cocaine. 

“These results suggest that catalytic antibodies have the 

unique potential both to treat the acute effects of cocaine 

overdose and to block some of the chronic reinforcing 

effects of abuse,” Dr. Landry says. “A humanized version 

of the antibody mAB 15A10 could be useful either as an 

emergency treatment for overdose or as part of a broader 

treatment program for addiction.” 
126

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6(3):274–279, 1998. 

• Fox, B.S., et al. Efficacy of a therapeutic cocaine 

vaccine in rodent models. Nature Medicine 

2(10):1129–1132, 1996. 

• Fox, B.S. Development of a therapeutic vaccine for 

the treatment of cocaine addiction. Drug and Alcohol 

Dependence 48:153–158, 1997. 

• Gorelick, D.A. Enhancing cocaine metabolism with 

butyrylcholinesterase as a treatment strategy. Drug 

and Alcohol Dependence 48:159–165, 1997. 

• Landry, D.W. Immunotherapy for cocaine addiction. 

Scientific American 276(2):42–45, 1997. 

• Mattes, C.E.; Belendiuk, G.W.; Lynch, T.J.; Brady, 

R.O.; and Dretchen, K.L. Butyrylcholinesterase: An 

enzyme antidote for cocaine intoxication. Addiction 

Biology 3:171–188, 1998. 

• Mets, B.; Winger, G.; Cabrera, C.; Seo, S.; Jamdar, 

S.; Yang, G.; Zhao, K.; Briscoe, R.J.; Almonte, R.; 

Woods, J.H.; and Landry, D.W. A catalytic antibody against cocaine prevents cocaine’s reinforcing 

and toxic effects in rats. Proceedings of the National 

Academy of Sciences 95:10176–10181, 1998. 

• Sparenborg, S.; Vocci, F.; and Zukin, S. Peripheral 

cocaine-blocking agents: New medications for cocaine 

dependence. Drug and Alcohol Dependence 48:149–

151, 1997. 

• Xie, W.; Altimirano, C.V.; Bartels, C.F.; Speirs, R.J.; 

Cashman, J.R.; and Lockridge, O. An improved 

cocaine hydrolase: The A328Y mutant of human 

butyrylcholinesterase is 4-fold more efficient. 

Molecular Pharmacology 55(1):83–91, 1999. 
127

Research Findings

Coping Skills Help Patients Recognize and Resist the Urge 

to Use Cocaine

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 13, Number 6 (March, 1999)

For some cocaine abusers, urges to use cocaine come out 

of the blue. But more often the urge is associated with an 

identifiable situation that triggers drug use. A behavioral 

science research study supported by NIDA has led to the 

development of a treatment technique that helps cocaine 

users control their drug use by recognizing and coping 

with these high-risk situations. 

Dr. Damaris Rohsenow, Dr. Peter Monti, and their colleagues at Brown University’s Center for Alcohol and 

Addiction Studies in Providence, Rhode Island, have 

developed a cocaine-specific coping skills training (CST) 

technique that can be used as part of a treatment program 

to help cocaine abuse patients identify situations that trigger 

their urges to 

use cocaine and modify their behavior to avoid drug use. 

In the study, patients who received CST as part of treatment “had significantly shorter and less severe relapses 

during the 3-month followup period than did patients 

who received standard treatment,” Dr. Rohsenow says. 

Patients who received CST were taught to identify highrisk situations, called triggers, associated with drug use. 

These triggers were broadly categorized into topic areas 

such as anger, money, frustration, or depression. Patients 

then focused on specific personal examples of triggers 

and analyzed the sequence of actions, called a “behavioral 

chain,” that led to drug use in those situations. 

Patients learned how to avoid or modify the trigger situation when possible. “For example, if a money trigger is 

associated with getting a paycheck, they might arrange for 

their paycheck to be directly deposited in their bank. Or 

if drug use is associated with their lunch break, patients 

could eat with a group of coworkers rather than going out 

alone,” Dr. Rohsenow explains.

For situations in which the trigger could not be avoided, 

patients developed a repertoire of cognitive and behavioral 

skills to modify the behavioral chain and reduce their personal risk of drug use. “A phone call from an ex-spouse 

might be an ‘anger’ trigger that can’t be avoided. But 

patients can use coping skills training to change how they 

behave in response to the call. They can ‘talk out’ their 

anger with friends or do something physical like go out 

and play basketball,” Dr. Rohsenow says. 

The study involved 128 male and female patients selected 

from 2 drug abuse treatment facilities. Standard treatment 

at these facilities is an abstinence-based program that combines the principles of the Alcoholics Anonymous 12-step 

program with educational information presented in group 

formats, individual counseling sessions, and family or 

marital therapy. Roughly half the patients received standard treatment plus eight 1-hour sessions of CST. The 

other half received standard treatment plus eight 1-hour 

sessions of meditation-relaxation training (MRT), a procedure that often is used as part of treatment programs but 

has no significant effect on substance use. The MRT procedure assured that all patients in the study spent the same 

amount of time in contact with therapists. 

The patients were evaluated at 1 and 3 months following treatment. Roughly 45 percent of patients from each 

group suffered relapses following treatment, but relapsing 

CST patients averaged only 6.2 days of drug use compared 

with more than 13 days of cocaine use for patients who 

received MRT. 

The improvement in outcome for most CST patients 

was far better than these average figures suggest, Dr. 

Rohsenow points out, because one relapsed CST patient 

used cocaine for 49 out of 90 days in the followup period. 

The other CST patients averaged only 3.8 days of drug 

use. 

Among CST patients, the longest binges averaged 2.8 

days —less than half as long as the binges for the other 

patients, which lasted an average of 6 days. 

“Patients with CST training were able to change the way 

they thought and then change the way they behaved in 

situations that posed a risk of relapse,” Dr. Rohsenow 

says. 

Source 

• Monti, P.M.; Rohsenow, D.J.; Michalec, E.; Martin, 

R.A.; and Abrams, D.B. Brief coping skills treatment 

for cocaine abuse: Substance use outcomes at three 

months. Addiction 92(12):1717–1728, 1998. 

Coping skills training can help 

patients identify situations that trigger 

their urges to use cocaine and modify 

their behavior to avoid drug use.
Research Findings

128

Cocaine Activates Different Brain Regions for Rush Versus Craving

By Steven Stocker, NIDA NOTES Contributing Writer 

Using a brain imaging technology called functional magnetic resonance imaging (fMRI), NIDA-funded scientists 

have shown that different parts of the human brain are 

activated during cocaine “rush” versus cocaine craving. 

This technology is also being used to identify the parts of 

the brain that become active when a cocaine addict sees 

or hears environmental stimuli that trigger a craving for 

cocaine. These studies may be useful in the development 

of medications for treating cocaine addiction, because they 

help scientists pinpoint specific brain regions that need to 

be targeted by medications for countering cocaine’s multiple effects. 

Developed in the early 1990s, fMRI can visualize areas of 

the brain that many researchers believe are regions with 

increased nerve cell activity. Images can be produced 

quickly, enabling volunteers to describe their sensations 

at the same time that the images are being produced. As a 

result, fMRI allows researchers to closely associate regions 

of brain activity with specific emotions. 

Using fMRI, Dr. Hans Breiter and his colleagues at the 

Massachusetts General Hospital in Boston administered 

cocaine to cocaine-addicted volunteers whom they had 

trained to continuously rate their feelings of rush, high, 

low, and craving. The rush experience involved elevated 

heart rate and sweating, along with feelings of “speeding” 

or “being out of control.” The high experience was generally associated with feelings of euphoria, self-confidence, 

well-being, and sociability. The low experience involved 

negative emotions, such as anxiety, paranoia, and the loss 

of any feelings of pleasure. Craving was defined as the 

desire to use more cocaine. 

Rush and high both peaked within 3 minutes after the 

volunteers received cocaine. While the rush dissipated 

quickly, the high decreased more gradually. The low slowly increased, peaking 11 minutes after receiving cocaine, 

and craving peaked 12 minutes after receiving cocaine. 

The researchers determined that certain areas of brain 

activity were associated more with feelings of rush, and 

other areas were associated more with feelings of craving. 

“We only looked at brain regions associated with rush 

and craving because these were the two ratings that were 

the most distinct from each other,” says Dr. Breiter. “The 

rush scores were coming down at the same time that the 

craving scores were going up.” 

Rush was associated with activity in many areas of the 

brain, including the ventral tegmentum in the midbrain 

and the basal forebrain, or base of the forebrain. This 

activity peaked shortly before the volunteers reported that 

they had reached peak rush, and then the activity began to 

dissipate, much like the reported rush. 

No areas of brain activity directly paralleled the ratings 

for craving. What did seem to be associated with craving 

was the fact that activity in a few regions continued after 

all others had stopped. These regions included the nucleus 

accumbens and the right parahippocampal gyrus, both in 

the forebrain.

“Craving may not be mediated by one or two distinct 

brain regions,” says Dr. Breiter. “Rather, the craving that 

occurs shortly after taking cocaine may be due to a change 

in the pattern of brain activity over time. Many brain 

regions are active when the volunteers report feelings of 

rush. Over time, however, only a few brain regions remain 

activated. This change in activation pattern may be what 

causes the subjective experience of craving.” 

These results bear out similar findings in animals. Some 

of the regions of activity that were associated with rush or 

craving have been implicated in animal studies as being 

important in producing the pleasurable feelings associated 

with cocaine use. The regions include the ventral tegmentum, nucleus accumbens, and basal forebrain. “This study 

provides a bridge between the animal studies and the 

human studies,” says Dr. Breiter. 

Volume 13, Number 5 (February, 1999)

Dr. Hans Breiter, left, Dr. David Kennedy, center, and Dr. Randy 

Gollub will use images produced by this magnetic resonance imaging scanner to identify areas of the brains of cocaine-addicted volunteers that become activated during cocaine rush and craving. 
129

Instead of investigating the craving that occurs after 

cocaine is injected, Luis Maas, Dr. Scott Lukas, Dr. Perry 

Renshaw, and their colleagues at McLean Hospital in 

Belmont, Massachusetts, used fMRI to investigate brain 

activation during what is known as cue-induced craving. 

In this type of craving, cocaine-related stimuli or cues 

from the environment, such as seeing someone cook crack 

cocaine or smoke a crack pipe, trigger memories of the 

drug-taking experience, which elicit craving. “What we 

think is happening is not unlike what happened in the 

Pavlov’s dog experiment,” says Dr. Lukas. In this experiment, Russian physiologist Dr. Ivan Pavlov rang a bell 

shortly before he presented food to hungry dogs. After 

many pairings of the bell with food, Dr. Pavlov found 

that merely ringing the bell caused the dogs to salivate. 

In the McLean Hospital experiment, the researchers 

showed crack cocaine abusers a 10-minute videotape that 

consisted of segments with crack cocaine-related images 

and sounds alternating with segments that involved neutral stimuli, such as images of butterflies. When the volunteers saw the cocaine-related segments, two brain regions 

in particular became activated—the anterior cingulate and 

the left dorsolateral prefrontal cortex, both in the forebrain. However, when the volunteers saw the neutral segments, these regions remained inactive. “The brain regions 

that became active during the cocaine-related portions of 

the videotape are associated with changes in mood state 

and with positive reinforcement. They are also in an area 

of the brain where memories are stored,” says Dr. Lukas. 

“Consequently, we think that we are seeing the ‘turning 

on’ of cocaine-related memories.” 

These results are consistent with a previous study conducted by Dr. Steven Grant, Dr. Edythe London, and their 

colleagues in NIDA’s Division of Intramural Research. 

This study utilized a different imaging technology called 

positron emission tomography (PET) that, like fMRI, 

produces images of brain regions with increased nerve cell 

activity but takes longer to produce these images. 

In that study, as in the McLean Hospital study, the 

researchers exposed cocaine abusers to cocaine-related 

stimuli, such as equipment used for snorting cocaine powder, plus a videotape showing people snorting cocaine and 

smoking crack. After the volunteers reported that they felt 

cocaine craving, the PET images showed increased nerve 

cell activity in certain brain regions, including the two 

identified in the McLean Hospital study. 

The fact that brain imaging techniques can visualize brain 

regions associated with the subjective effects of cocaine 

could be particularly useful to scientists developing medications for treating cocaine addiction, according to Dr. 

Joseph Frascella, chief of NIDA’s Etiology and Clinical 

Neurobiology Branch. Earlier studies with animals have 

provided good indication of which regions are affected by 

cocaine, he says. “However, it is difficult to assess craving 

or the subjective feelings of rush or euphoria in animals,” 

he says. “You can’t exactly ask an animal, ‘How much are 

you craving at this point?’” The value of fMRI in particular is that human volunteers can tell researchers what they 

are feeling and at the same instant the researchers can see 

increased activity in brain regions that are associated with 

that subjective state, says Dr. Frascella. “This type of work 

is helping scientists identify the brain systems that need to 

be targeted by medications that counter cocaine’s subjective effects,” he says. 

Sources 

• Breiter, H.C.; et al. Acute effects of cocaine 

on human brain activity and emotion. Neuron

19(3):591–611, 1997. 

• Grant, S.; et al. Activation of memory circuits during cue-elicited cocaine craving. Proceedings of the 

National Academy of Sciences USAj 93:12040–12045, 

1996. 

• Maas, L.C.; et al. Functional magnetic resonance 

imaging of human brain activation during cueinduced cocaine craving. American Journal of 

Psychiatry 155(1):124–126, 1998. 

Dr. Scott Lukas, left, and Dr. Perry Renshaw discuss the brain 

scan of a cocaine-addicted volunteer that shows which brain regions 

were activated when the volunteer watched a videotape of cocainerelated images. Two regions that became activated are circled on 

the brain scan shown at right. 
Research Findings

130

Cocaine Abuse May Lead To Strokes and Mental Deficits

By Steven Stocker, NIDA NOTES Contributing Writer

Volume 13, Number 3 (July, 1998)

In 1977, a 43-year-old man came to an emergency room 

in New York City after having injected cocaine into a 

muscle in his left arm. Between 1 and 2 hours after the 

injection, he had begun having trouble speaking and was 

weak in his right arm and leg. After performing a brain 

scan, doctors at the hospital determined that the man had 

had a stroke on the left side of the brain. Although the 

man also abused other drugs, the fact that the stroke had 

occurred shortly after he had injected cocaine suggested 

that cocaine had contributed to the stroke. This case was 

one of the earliest verified reports of a stroke associated 

with cocaine use. In their report, the doctors concluded, 

“If, in fact, cocaine played a causal role [in the stroke], we 

anticipate that more strokes will be seen among the many 

abusers of this agent in American cities.”

Their prediction turned out to be correct. In subsequent 

years, cocaine-related strokes became more frequent, 

particularly in the mid-1980s after the advent of crack 

cocaine. These strokes involved sudden dramatic reductions in blood flow to areas of the brain, resulting in neurological symptoms, such as paralysis, loss of speech, and 

dementia.

In the late 1980s, researchers began noticing another type 

of blood flow disturbance associated with cocaine use. 

This second type involved less dramatic but more persistent reductions in cerebral blood flow that could lead to 

difficulties concentrating, slowed thought processes, and 

memory deficits.

Until recently, scientists could only theorize about how 

cocaine was causing these cerebral blood flow disturbances. Now NIDA-supported scientists have learned more 

about how cocaine causes strokes and produces the persistent blood flow deficits. Other NIDA-funded researchers 

have observed that the brain damage caused by these deficits interferes with drug treatment, and they are studying 

how to modify treatment to accommodate patients with 

this type of brain damage.

Short-term Reductions in Blood Flow

Using magnetic resonance angiography (MRA), an imaging technique that shows blood flow in large- and medium-sized arteries in the brain, NIDA-funded researchers 

Dr. Marc Kaufman and Dr. Jonathan Levin and their 

colleagues at McLean Hospital in Belmont, Massachusetts, 

have demonstrated that cocaine use temporarily narrows 

arteries in the brain, thereby reducing the blood supply to 

various brain regions. Researchers had suspected this for 

many years because they knew that cocaine could cause 

vasoconstriction, or narrowing of blood vessels, in the 

heart and other regions of the body. This study conclusively demonstrated this effect in the human brain.

The researchers administered either cocaine or a placebo 

solution to 24 men, ages 24 to 34. The volunteers had 

used cocaine occasionally but were not dependent on the 

drug. The cocaine doses administered were relatively low, 

resulting in cocaine blood levels that were at the low end 

of the range typically experienced during cocaine abuse.

Images of the brain were obtained before and 20 minutes 

after the cocaine was administered. By comparing before 

and after images, the researchers could see where blood 

vessels were narrowed. Among the 7 men who received 

the placebo, only 1 showed blood vessel narrowing, but 

among the 9 men who received the lowest dose of cocaine, 

3 had vasoconstriction in several brain arteries. Among the 

8 men who received a higher dose, 5 showed this effect. 

The vasoconstrictions ranged from small reductions in 

Dr. Marc Kaufman (left) and Dr. Jonathan Levin of McLean

Hospital will review images from this brain scanner for signs of 

cocaine-related narrowing of the volunteer’s arteries.

© 1998 Allan E. Dines
131

blood vessel diameter to more significant obstructions of 

blood flow.

The more often the men had used cocaine in the past, the 

more likely the drug was to narrow blood vessels, which 

suggests that cocaine has a cumulative effect on brain 

arteries. “This cumulative effect may start with as few as 

5 to 10 exposures to cocaine,” says Dr. Kaufman. “As a 

result, people who use cocaine many times probably have 

a high incidence of vasoconstriction in their brains.”

One possible outcome of cocaine’s cumulative effect may 

be a stroke. As a result of many cocaine exposures, brain 

arteries may be more reactive to the chemical stimuli that 

normally cause them to constrict, Dr. Kaufman says. This 

constriction could substantially reduce the blood supply to 

a region for several minutes, thereby damaging nerve cells 

and possibly causing stroke-like symptoms. A more likely 

outcome of the cumulative effect would be persistent 

blood flow reductions to large areas of the brain. These 

reductions are less substantial than those that occur in a 

stroke and may not kill nerve cells, but they could cause 

thinking and memory deficits, says Dr. Kaufman.

Long-term Reductions in Blood Flow

Scientists began to observe that cocaine could cause 

persistent blood flow deficits in the brain in the mid1980s. NIDA-funded scientist Dr. Nora Volkow and 

her colleagues at the Brookhaven National Laboratory in 

Upton, New York, and at the University of Texas Health 

Science Center in Houston used another imaging technique called positron emission tomography (PET), which 

can show the flow of blood in the brain tissue rather than 

in the brain arteries, as MRA does. When the researchers 

compared PET scans of young adult cocaine-abusing men 

with scans of normal volunteers, they found that most of 

the abusers had less blood flow in some areas of the brain. 

When the researchers performed PET scans again 10 days 

later, the blood flow deficits were still there, even though 

the abusers had stopped using cocaine. Many of the volunteers had difficulties concentrating and performing 

simple calculations, which the researchers concluded were 

associated with the blood flow deficits.

Subsequently, other scientists verified that cocaine abusers had blood flow deficits in the brain and that these 

deficits persisted long after the individuals stopped abusing cocaine. Using a technique similar to PET called 

single photon emission computed tomography (SPECT), 

Dr. Tony Strickland of Charles R. Drew University of 

Medicine and Science in Los Angeles and the University 

of California, Los Angeles, School of Medicine and his 

colleagues took brain images of cocaine abusers who had 

abstained from cocaine for at least 6 months before evaluation. Even after this long period of abstinence, the images showed that the abusers still had blood flow deficits 

compared to control subjects, suggesting that the deficits 

may be long-term or perhaps even permanent.

In addition to taking brain images with SPECT, Dr. 

Strickland’s group also administered neuropsychological 

tests to the cocaine abusers. These tests detected many 

abnormalities that seemed to be associated with reduced 

activity in the parts of the brain affected by the reduced 

blood flow. These abnormalities included deficits in attention, memory, concept formation, and mental flexibility. 

The tests also showed that long-term cocaine abusers 

had trouble inhibiting inappropriate behaviors, a condition psychologists call disinhibition.

Dr. Levin, who worked on the MRA study with Dr. 

Kaufman, thinks that chronic cocaine abuse may lead to 

strokes and long-term blood flow deficits by accelerating 

atherosclerosis in brain arteries. Atherosclerosis is a thickening on the inside of blood vessels that some researchers 

believe makes the vessels more likely to go into vasospasm, 

which is a vasoconstriction that lasts for minutes rather 

than seconds. “Let’s say a blood vessel in a person’s brain 

has atherosclerosis as a result of some injury to the blood 

vessel. If the person takes a compound such as cocaine 

that causes vasoconstriction, the part of the blood vessel 

that is likely to go into spasm is the part with the atherosclerosis,” explains Dr. Levin. This vasospasm may then 

damage the inner lining of the blood vessel, which would 

further promote the development of atherosclerosis. If 

the person continues to take cocaine, more vasospasms 

would occur and hence more atherosclerosis. “It becomes 

a vicious cycle,” he says.

This would explain how cocaine could cause strokes. 

Eventually, the vasospasms induced by cocaine last so long 

that nerve cells die from a lack of blood. The explanation 

for the persistent blood flow deficits might be that the 

atherosclerosis is slowly clogging the inside of the blood 

vessels, thereby reducing blood flow. One piece of evidence 

in favor of this theory is that aspirin has been shown to 

reverse temporarily the cerebral blood flow deficits caused 

Dr. Tony Strickland of Charles R. Drew University of Medicine

and Science tests a volunteer for cocaine-related mental deficits.
132

by cocaine. Aspirin inhibits the formation of blood clots 

that are part of the atherosclerotic process.

Using a technology called transcranial Doppler sonography 

(TCD), Dr. Ronald Herning, Dr. Jean Lud Cadet, and 

colleagues in NIDA’s Division of Intramural Research in 

Baltimore have found evidence that cocaine abusers do 

indeed have significant atherosclerosis in their brain 

arteries. In TCD, very high frequency sound waves are 

bounced off the blood flowing in large arteries in the 

brain, and the characteristics of the reflected sound waves 

can be used to estimate the constriction of the arteries. 

“Our data suggest that cocaine abusers in their thirties 

have arteries that are as constricted as those of normal 

subjects in their sixties,” says Dr. Herning.

Mental Deficits

Drug treatment providers should be aware that mental deficits that develop in cocaine abusers as a result 

of reduced blood flow may hamper the ability of these 

patients to benefit from treatment, says Dr. Strickland. 

Some patients have trouble paying attention or remembering conversations; others disrupt the therapy by being 

disinhibited. They constantly interrupt the therapist, they 

begin tasks without waiting for all the instructions, and 

they may become aggressive.

Dr. Strickland recommends giving new drug abuse 

patients neuropsychological screening tests to identify 

their deficits. Once these deficits are identified, the therapist can modify the drug treatment to accommodate the 

deficits, he suggests. For example, if the patient has trouble 

paying attention and remembering, the therapist could 

present information in small segments and repeat each 

segment until the patient learns it. 

A major component of therapy is simply informing these 

patients that their long-term drug abuse has changed the 

way their brains function, Dr. Strickland says. “Some of 

these patients know that something is wrong but don’t 

know what it is,” he says. “They are relieved to learn that 

they’re not ‘crazy’ and that the source of their problems is 

that drugs have altered the way their brains process information. They also are relieved to learn that they can take 

steps to enhance their performance.”

“Compared to patients who have brain injury from motorcycle accidents, gunshot wounds, or other causes, drug 

abuse patients have considerably less impairment,” notes 

Dr. Strickland. “We’re successful in helping traumatic brain 

injury patients, and so the chances of helping patients with 

drug-induced brain injury are comparatively good.”

In addition to modifying drug abuse treatment to accommodate the mental deficits of cocaine abusers, NIDA 

scientists are also investigating the possibility of treating 

their blood flow and mental deficits with medications. 

TCD will be particularly useful for monitoring the blood 

flow effects of medications, says Dr. Herning. “TCD is 

a quick, easy, relatively inexpensive measure that can be 

used repeatedly, so you can give your subjects medications 

and monitor them weekly, which you cannot do with 

PET or SPECT.”

Sources

• Brust, J.C.M.; and Richter, R.W. Stroke associated with cocaine abuse? New York State Journal of 

Medicine 77:1473–1475, 1977.

• Herning, R.I.; King, D.E.; Better, W.; and Cadet, 

J.L. Cocaine dependence: A clinical syndrome requiring neuroprotection. Annals of the New York Academy 

of Sciences 825:323–327, 1997.

• Kaufman, M.J., et al. Cocaine-induced cerebral 

vasoconstriction detected in humans with magnetic 

resonance angiography. The Journal of the American 

Medical Association 279(5):376–380, 1998.

• Kosten, T.R.; Malison, R.; and Wallace, E. 

Neuropsychological abnormalities in cocaine abusers: Possible correlates in SPECT neuroimaging. In: Majewska, M.D., ed. Neurotoxicity and 

Neuropathology Associated with Cocaine Abuse. NIDA 

Research Monograph Series, Number 163. NIH 

Publication No. 96-4019. Pittsburgh, PA: Supt. of 

Docs., U.S. Govt. Print. Off., 1996, pp. 175–192.

• Strickland, T.L., et al. Cerebral perfusion and neuropsychological consequences of chronic cocaine use. 

Journal of Neuropsychiatry 5(4):419–427, 1993.

• Strickland, T.L.; Stein, R.A.; Khalsa-Denison, M.E.; 

and Andre, K. Neuropsychological effects of chronic 

cocaine use following sustained abstinence. Archives of 

Clinical Neuropsychology 11(5):456–457, 1996.

• Volkow, N.D.; Mullani, N.; Gould, K.L.; Adler, S.; 

and Krajewski, K. Cerebral blood flow in chronic 

cocaine users: A study with positron emission 

tomography. British Journal of Psychiatry 152:641–

648, 1988. 
Research Findings

133

Brain Scans Open Window To View Cocaine’s Effects on the Brain

By Neil Swan, NIDA NOTES Staff Writer 

Volume 13, Number 2 (July, 1998)

New NIDA-funded research supports a widely held theory 

that cocaine-induced euphoria is precipitated by blocking the normal flow of the chemical messenger dopamine 

in the brain. The findings also help clarify why cocaine 

addicts “binge” on the drug. A related study by the same 

research team challenges another theory about where in 

the brain this dopamine action occurs. 

Dopamine is a neurotransmitter, a chemical that carries messages from one nerve cell, or neuron, to another 

or from one functional section of the brain to another. 

This neurotransmitter is associated with body movement, awareness, judgment, motivation, and pleasure. 

Researchers believe it is responsible for the addictive 

effects of drugs such as cocaine. 

Dopamine flows from neurons into the synapses, or spaces 

between neurons, to form a temporary link that serves to 

transmit signals between neurons. Then, normally, after 

it has transmitted its signal to the neighboring neuron, 

it vacates these spaces, returning to the same neuron 

that released it in a recycling process called reuptake. 

Dopamine moves from the synaptic gap back inside the 

neuron by attaching to “transporter” molecules on the 

neuron’s surface. 

Cocaine, however, attaches to the same transporter binding sites as dopamine. This means that, when cocaine is 

introduced, dopamine cannot bind to the dopamine transporter and is stranded in the synapses. Thus, cocaine’s 

blocking action leads to an increase of dopamine levels in 

the synapses that, scientists believe, normally produce feelings of pleasure. Cocaine’s action intensifies these feelings 

into euphoria, studies show. 

Now, Dr. Nora Volkow of NIDA’s Regional 

Neuroimaging Center at Brookhaven National Laboratory 

in Upton, New York, has provided visual evidence to 

confirm this theory of how cocaine blocks the reuptake of 

dopamine. Dr. Volkow used brain images to show that, 

in cocaine addicts, dopamine is directly involved in the 

euphoria that reinforces the drug abuser’s desire to take 

drugs. 

“The results affirm the theory that dopamine transporter 

blockade plays a crucial role in the rewarding and reinforcing properties of cocaine in humans,” she says, adding 

that this role may explain why cocaine addicts sometimes 

binge uncontrollably. 

Dr. Volkow theorizes that cocaine binging may result 

from the corruption of primeval survival-of-the-species 

urges that are controlled by dopamine. Dopamine activity 

is known to control urges to begin—and to repeat—acts 

that are necessary for survival such as eating, drinking, and 

engaging in sex. Satisfying these urges results in pleasure 

or gratification. “Pleasure is a natural reinforcer to increase 

the probability that a species will engage in a given behavior and continue that behavior,” she says. Once these 

urges have been satisfied, the body’s normal response is 

satiety or “that’s enough.” Repeated cocaine use, however, 

turns off this normal satiety response so that users continue craving and drug seeking behavior, she suggests. This 

short-circuiting of the satiety response could explain 

why cocaine abusers binge even in the face of powerful 

negative side effects, she adds. 

The neurotransmitter dopamine transmits brain signals by flowing 

from one neuron into the spaces between neurons and attaching to 

a receptor on another neuron. Normally, dopamine then is recycled 

back into the transmitting neuron by a transporter molecule on the 

surface of the neuron. But if cocaine is present, the drug attaches to 

the transporter and blocks the normal recycling of dopamine, 

causing an increase of dopamine levels in the spaces between 

neurons that leads to euphoria. 

Cocaine in the Brain
134

“When satiety is suppressed, the pleasurable properties of 

cocaine serve as a trigger for activating brain pathways that 

will then maintain the drug-consuming behavior,” she 

concludes. 

Dr. Volkow used a brain imaging technology called 

positron emission tomography (PET) to study 17 longterm users of cocaine. She found that the intensity of 

the cocaine-induced high or euphoria that the volunteers 

reported was related directly to cocaine’s ability to block 

the dopamine transporter system. 

Using intravenous injections of cocaine at doses comparable to those typically used by abusers, Dr. Volkow 

found that cocaine blocked between 60 percent and 77 

percent of the dopamine transporter binding sites in the 

brains of the addicts. She found that at least 47 percent of 

the binding sites had to be blocked by cocaine before the 

volunteers said they felt a drug-induced high. 

A related study by Dr. Volkow measured drug responses 

of cocaine addicts and of nonaddicted volunteers who had 

not developed craving for the drug. In that study, she used 

PET imaging to compare responses to intravenous administration of methylphenidate, a stimulant drug that, like 

cocaine, increases synaptic levels of dopamine. 

Many researchers have theorized that elevated dopamine 

levels associated with the reinforcing effects of cocaine 

occur in the brain region called the nucleus accumbens. 

However, Dr. Volkow found that cocaine-dependent 

volunteers experienced decreased, not increased, levels of 

dopamine release, compared to nonaddicted volunteers, 

in the striatum, where the nucleus accumbens is located. 

Instead, addicts’ response to methylphenidate was greater 

than that of nonaddicts in the thalamus, a brain region 

that carries sensory signals to the cerebral cortex. This 

thalamic response in the cocaine addicts was associated 

with cocaine craving and was not seen in nonaddicted 

volunteers. “Thus, our findings challenge the notion that 

addiction involves an enhanced dopamine response to 

cocaine in the striatum,” Dr. Volkow reports. The data 

suggest that the brain’s thalamus region may have an 

addiction-related role in dopamine levels and functions, 

she says. 

Sources 

• Volkow, N.D., et al. Relationship between subjective 

effects of cocaine and dopamine transporter occupancy. 

Nature 386:827–830, 1997. 

• Volkow, N.D.; Wang G.-J.; Fowler, J.S.; Legan, J.; 

Gatley, S.J.; Hitzeman, R.; Chen, A.D.; Dewey, S.L.; 

Pappas, N. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. 

Nature 386:830–833, 1997. 
Research Findings

135

NIDA Brain Imaging Research Links Cue-Induced Craving to 

Structures Involved in Memory

By Neil Swan, NIDA NOTES Staff Writer

For years, drug abuse researchers have known that when addicts are exposed to drug-related cues, such as the sight of drug 

Volume 11, Number 5 (November/December, 1996)

paraphernalia or even a 

drug-using companion, 

these stimuli can spark 

powerful drug craving. 

Using brain-imaging 

techniques, scientists are 

literally seeing the changes 

that these environmental 

cues trigger in the brain as 

they are taking place. 

Researchers in NIDA’s 

Division of Intramural 

Research (DIR) have 

recently published brain 

imaging findings that 

show that cue-induced 

drug craving is linked to 

distinct brain systems that 

are involved in memory. 

“Drug craving is a central 

aspect of addiction and 

poses an obstacle to treatment success for many individuals,” says NIDA Director Dr. Alan I. Leshner. “Twenty 

years of neuroscience research have brought us to where 

we can actually see increases in specific brain activity that 

are linked to the experience of craving. If we can understand the mechanisms that cause craving in people addicted to cocaine or other drugs, more effective treatment 

strategies can be developed that counteract craving.” 

Using positron emission tomography (PET), Dr. Edythe 

D. London and her colleagues at DIR’s Addiction 

Research Center (ARC) in Baltimore produced brain 

images showing that, in people who have used cocaine, 

cocaine-use cues spark increased glucose metabolism in 

brain regions that are associated with memory. Increased 

glucose metabolism indicates enhanced neural activity. 

By questioning the volunteers whose brains were scanned, 

researchers correlated computer-screen images with the 

cocaine users’ responses about intensity of craving sensations. To make the correlation, the brain images were 

examined for color changes that are calibrated to show 

areas of increased glucose metabolism. 

In the study, DIR researchers compared metabolic activity 

in the brains of 13 volunteers who had used cocaine with 

activity in the brains of a control group of 5 volunteers 

who had never used cocaine. The scans were taken after 

the groups were exposed to both cocaine-related cues and 

neutral cues. The cocaine-related stimuli consisted of 

observing drug paraphernalia and viewing a videotape of 

cocaine users. 

The cocaine-user group responded to the cocaine-related 

cues, but not to the neutral cues, with increased glucose 

metabolism, which was visible in the PET images and 

with their own reports that they were experiencing craving. The greater the reports of craving, the greater the 

metabolic activity in three key areas of the brain, the 

researchers found. The volunteers who had never used 

cocaine reported no cocaine cue-induced craving and 

showed no visual signs of cue-induced brain activity. 

Among the brain regions 

activated by the cocaine 

cues were the dorsolateral 

prefrontal cortex, amygdala, 

and cerebellum, which 

are all involved in aspects 

of memory and learning. The amygdala has 

been linked to emotional 

aspects of memory. The 

findings suggest that 

a neural network involving 

these brain regions 

integrates the emotional 

and cognitive aspects of 

memory and reacts to 

environmental cues and 

memories by triggering 

cocaine craving. 

“These three areas show 

cue-induced activity 

changes that are highly 

correlated with the behavioral measure, which is 

craving,” says Dr. London, director of the NIDA Brain 

Imaging Center and initiator of the study. “Thus, we have 

identified brain circuits that may be targets for pharmacotherapy or other treatments. We now have a practical 

system for testing potential interventions. This system 

overcomes the limitations of an addict’s own subjective 

evaluations of craving sensations by using the PET scanDr. Edythe D. London, director 

of NIDA’s new Brain Imaging 

Center, initiated the craving study

that has found links between cueinduced craving and the brain 

structures involved in memory. A 

pharmacologist, she began brain 

imaging research in 1979 and 

came to DIR in 1981.

Dr. Steven Grant is lead investigator on the craving study. The study 

continues with the latest PET 

imaging scanner at the Center,

probing how drug-related cues may 

disrupt normal memory functions.
136

ner to see, objectively, actual responses within the brain 

that correlate to craving.” 

Until now, the three brain regions identified by the 

researchers have been associated with memory functions, 

but not with drug craving, says Dr. Steven Grant, the 

study’s lead investigator. These new findings support the 

hypothesis that memory may be more critical to drug 

craving than is the traditional concept of reinforcement. 

“The amygdala, which is involved in giving memories 

emotional color, puts an emotional aspect on the cueinduced craving sensations,” he adds. 

The current research into cue-induced craving continues 

with new PET scanning equipment recently installed at 

the ARC. 

Dr. London and her colleagues are using the new scanner 

to test whether cue-induced craving impairs an addict’s 

ability to perform simple daily tasks. Preliminary findings 

confirm the hypothesis that cues can intrude into working 

memory functions, producing distracting daydreams or 

cocaine-oriented thoughts, says Dr. Grant. “Activation, by 

drug-related cues, of brain regions that integrate the emotional and cognitive parts of memory could contribute to 

one of the hallmarks of addiction—the excessive focus on 

activities that lead to further drug use,” Dr. London says.

Sources 

• Grant, S.; London, E.D.; Newlin, D.B.; Villemagne, 

V.L.; Liu, X.; Contoreggi, C.; Phillips, R.L.; Kimes, 

A.S.; and Margolin, A. Activation of memory circuits 

during cue-elicited cocaine craving. Proceedings of the 

National Academy of Sciences 93:12040–12045, 1996. 

• London, E.D., et al. Cocaine-induced reduction of 

glucose utilization in human brain. Archives of General 

Psychiatry 47(6):567–574, 1990. 

• Stapleton, J.M., et al. Cerebral glucose utilization in 

polysubstance abuse. Neuropsychopharmacology 

13(1)21–31, 1995. 

PET scans conducted at NIDA’s Brain Imaging Center reveal selective activation of brain circuits during cocaine craving. Scans from 

volunteers who experienced a high level of cue-induced cocaine craving show activation of brain regions implicated in several forms of 

memory. The scans at right show activation of the dorsolateral prefrontal cortex (DL), which is important in short-term memory, and

the amygdala (AM), which is implicated in emotional influences on

memory. When these volunteers were exposed to neutral (non-drugrelated) cues, this activation was not seen (scans at left).
Research Findings

137

Anxiety and Stress Found to Promote Cocaine Use in Rats

By John A. Bowersox, NIDA NOTES Contributing Writer 

Volume 11, Number 4 (September/October, 1996)

Although cocaine users typically report that the drug 

enhances their feelings of well-being and reduces anxiety, 

cocaine also is known to bring on panic attacks in some 

individuals. What’s more, studies have shown that longterm cocaine use leads to increased anxiety. Severe anxiety, 

along with restlessness and agitation, is also among the 

major symptoms of cocaine withdrawal. 

Recent NIDA-funded research now suggests that there 

could be a different aspect to the relationship between 

cocaine use and anxiety: anxiety and stress may be among 

the factors that lead to cocaine abuse. 

In separate studies that may prove useful for understanding the behavioral and biological mechanisms involved in 

the initiation of cocaine use and dependence, Dr. Nick 

E. Goeders of Louisiana State University in Shreveport 

and Dr. Klaus Miczek of Tufts University in Boston have 

reported that rats under stress learn to give themselves 

cocaine more quickly than do nonstressed rats. 

Both studies involved exposing rats to stressful situations 

and then assessing how quickly the animals learn to 

self-administer cocaine by pressing a bar in the testing 

chamber. Cocaine doses were at first very low but were 

increased gradually to determine the minimum dose at 

which the rat would learn the cocaine self-administering 

task. 

In Dr. Goeders’ experiment, the level of stress the rats 

were under was determined by measuring levels of the 

stress hormone corticosterone in their blood. “It looks like 

corticosterone may make them more sensitive to cocaine,” 

says Dr. Goeders, who found that rats with the highest 

levels of corticosterone learned the cocaine self-administration 

task at doses far lower than did rats with low levels of the 

stress hormone. 

Initially, three groups of rats learned that if they pressed a 

bar in the testing chamber they would be rewarded with 

food pellets. Environmental stress was then introduced by 

periodically delivering very brief (one thousandth of a 

second) electric shocks to the animals’ feet. 

One group received random footshocks that were delivered 

noncontingently—that is, whether or not the animals 

pressed the food bar. Another group also received random 

shocks but only after the food bar was pressed. The third 

group served as the control and received no footshocks. 

As measured by levels of corticosterone in their blood, the 

group that received random, noncontingent footshocks 

experienced a significantly higher level of stress than did 

either of the other two groups. 

Each group of animals was then given the opportunity to 

self-administer a cocaine solution by pressing a second bar 

in the testing chamber. Rats in the noncontingent shock 

group required only half as much cocaine as animals in the 

other two groups did to learn to press the bar for the drug. 

Instead of footshocks, Dr. Miczek’s experiment employed 

a “social stress” design in which a rat is exposed to, but 

shielded from, a more aggressive rat. “Although the first 

animal is protected from the aggressive rat by a screen and 

cannot be injured, it still is threatened,” explains 

Dr. Miczek. 

A variety of physiological indicators of stress, including 

increased blood pressure, heart rate, and plasma corticosterone levels, confirmed that animals presented with this 

situation experienced stress. Dr. Miczek reports that the 

stressed rats in his experiment learned to self-administer 

cocaine twice as fast as did animals that were not exposed 

to the stressor. 

As strong as his and Dr. Goeders’ findings appear to 

be, however, he cautions that further studies are needed 

before broad conclusions about the association between 

stress and vulnerability to cocaine abuse can be made. 

The stressed rats in the experiment 

learned to self-administer cocaine 

twice as fast as did animals that were 

not exposed to the stressor.

Research also is important for 

understanding how external factors 

may make some individuals more 

vulnerable to cocaine abuse.
138

“Support for the notion that stressors sensitize animals to 

self-administration of drugs remains controversial,” says 

Dr. Miczek. He adds that certain important stressors, such 

as being threatened, have been shown to activate the same 

dopaminergic brain region that cocaine self-administration 

is known to activate. Although the recent studies report 

strong correlations between stress and how quickly rats 

learn to self-administer cocaine, they do not provide direct 

evidence of a biological mechanism through which this 

occurs, he notes. 

Dr. Goeders says that his laboratory is trying to provide 

such evidence by blocking corticosterone receptors in the 

rat brain and then performing the same studies of stress 

and cocaine self-administration described above. If the 

stress hormone is responsible for increasing the rate at 

which stressed rats learn to self-administer cocaine, he 

explains, blocking the hormone’s brain receptors should 

block the effect of the hormone. 

“We’re trying to determine if a specific type of corticosterone receptor mediates the effect of stress on cocaine 

self-administration.” These studies could help scientists 

gain a better understanding of the biology of initiation of 

cocaine use and abuse, he says. 

Dr. Roger Brown, who heads NIDA’s Behavioral 

Neurobiology Research Branch, adds that this kind of 

research also is important for understanding how external 

factors may make some individuals more vulnerable to 

cocaine abuse. These studies shed light on “the situations 

or conditions that contribute to drug abuse,” he says. “In 

humans, we know that there are factors beyond drug/

brain receptor interactions that affect drug-taking behavior.” In these studies, he adds, scientists have begun to 

address how one of these possible factors, stress, interacts 

with the biochemical pathways known to be involved in 

cocaine abuse. 

Sources 

• Goeders, N.E., and Guerin, G.F. Non-contingent 

electric footshock facilitates the acquisition of 

intravenous cocaine self-administration in rats. 

Psychopharmacology 114:63–70, 1994. 

• Goeders, N.E. Potential involvement of anxiety in 

the neurobiology of cocaine. Annals of the New York 

Academy of Sciences 654:357–67, 1992. 

• Miczek, K.A.; Hubbard, N.; and Cantuti-Castelvetri, 

I. Increased cocaine self-administration after social 

stress. Neuroscience Abstracts 21:1954 (Abstract 

Number 766.9), 1995. 
139

Cocaine Affects Men and Women Differently, NIDA Study Shows

By John A. Bowersox, NIDA NOTES Contributing Writer 

Volume 11, Number 1 (January/February, 1996)

A recent NIDA-funded study suggests that gender differences will become an increasingly important consideration in drug abuse treatment strategies. The study by 

researchers affiliated with Harvard Medical School found 

that cocaine affects men and women differently and that 

hormonal fluctuations play an important role in women’s 

responses to the drug.

In the study, Dr. Scott E. Lukas and his colleagues at the 

Alcohol and Drug Abuse Research Center in Belmont, 

Massachusetts, measured a variety of responses to cocaine 

in six male and six female volunteers. On separate days, 

the volunteers snorted single doses of cocaine and placebo 

powder in equal amounts relative to their body weights. 

The men were tested once, but the women were tested 

at two different times during their menstrual cycle: once 

during their follicular phase and again during their luteal 

phase. The follicular and luteal phases, respectively, correspond to the times before and after ovulation. The 

researchers calculated the phases of each woman’s cycle 

from the onset of menstruation:

• Dose 1 (midfollicular phase) was given 5 to 9 days 

after the onset of menstruation; 

• Dose 2 (midluteal phase) was given 18 to 22 days 

after the onset of menstruation. 

The researchers found that at both points in the menstrual 

cycle the women were much less sensitive to the drug than 

the men were. The men in the study had significantly more 

episodes of euphoria, or good feelings, and dysphoria, or 

bad feelings. When asked to rate the severity of their 

dysphoria, the men judged the bad feelings to be more 

unpleasant than the women did. The men also experienced greater heart rate and blood pressure increases and 

detected cocaine’s effects sooner than the women did. 

Although the men and women received equivalent doses 

of cocaine, women had lower levels of the drug in their 

blood than the men; their cocaine blood levels were even 

lower when they took the drug during the luteal phase of 

their menstrual cycle.

Dr. Lukas says that differences in the speed with which 

cocaine is metabolized may account for the drug’s different effects in men and women. In the body, cocaine is 

broken down into inactive metabolites by enzymes known 

as cholinesterases. Although men have higher levels of 

these enzymes in their blood plasma, women have higher 

levels of a type of cholinesterase enzyme found in red 

blood cells, Dr. Lukas explains. The red blood cell enzyme 

metabolizes cocaine much more actively than the plasma 

enzyme does.

Physical changes that occur during the menstrual cycle 

also may contribute to women’s decreased sensitivity to 

intranasal cocaine, says Dr. Lukas. The increase in certain 

hormone levels during the luteal phase causes women’s 

mucous membranes, including those that line the nasal 

passages, to secrete more mucus. Dr. Lukas says that the 

increased mucus may act as a barrier to the absorption 

of cocaine when women snort the drug during the luteal 

phase of their menstrual cycle.

“We believe that the gender differences in cocaine’s effects 

that we observed are due to a combination of metabolic 

differences and the greater physical barrier to cocaine 

absorption created by the increase in mucosity,” says Dr. 

Lukas. He adds that other as yet unknown factors could 

also help produce cocaine’s differing effects.

Dr. Lukas says the findings, which he presented at the 

1994 meeting of the College on Problems of Drug 

Dependence, might help explain, at least from a physiological perspective, why the prevalence of cocaine use 

among women has traditionally been much lower than 

it has been among men. According to the National 

Household Survey on Drug Abuse, approximately 3.1 

million men and 1.4 million women used cocaine at least 

once during 1993. Women also appear to take cocaine less 

frequently than men do. The 1993 survey, which was 

conducted by the Substance Abuse and Mental Health 

Services Administration, estimates that about 365,000 

men compared with 111,000 women used cocaine at least 

once a week.

Many women have reported that they did not get high 

when they first tried cocaine, says Dr. Lukas, adding that 

women’s low sensitivity to the drug combined with its 

high price create a strong disincentive to its continued use. 

On the other hand, he says, some women may become 

heavy users because they need to take more cocaine to get 

the same effect as men.

If further studies substantiate Dr. Lukas’ findings, they 

could have important implications for the treatment of 

Research Findings
140

cocaine abusers, says Dr. Elizabeth Rahdert, a research 

psychologist in NIDA’s Division of Clinical and Services 

Research.

“Therapists would have to realize that for women, the 

response to cocaine will be different at different times 

of the month and not a steady state as it is for men,” 

she says.

Presumably, she adds, patterns of craving and response to 

withdrawal could also fluctuate with a woman’s menstrual 

cycle, and treatment professionals would have to recognize 

that women could be more vulnerable to relapse at different points in their cycle. Furthermore, treatment strategies 

designed to address male usage patterns would have to be 

modified in accordance with women’s usage patterns.

Dr. Lukas’ work reflects NIDA’s increased interest in 

examining the gender-specific effects of drug abuse. Basic 

research findings such as the discovery that sex hormones 

can interact with neurotransmitters during normal brain 

functioning have fueled this interest.

“Previously, drug abuse research on women focused 

mainly on issues related to pregnancy and the effects of 

drug abuse on the developing fetus,” says Dr. Cora Lee 

Wetherington, a psychologist in NIDA’s Division of Basic 

Research.

“More recently, we’ve seen a shift with the realization 

that the treatment needs of women may be different from 

those of men. Although issues related to childbearing 

and child-rearing are still important areas of drug abuse 

research, researchers are questioning whether treatment 

strategies that were developed through research conducted 

largely on male subjects are appropriate for women,” says 

Dr. Wetherington.

Source

• Lukas, S.E.; Sholar, M.B.; Fortin, M.; Wines, J.D.; 

Kragie, L.; and Mendelson, J.H. Sex differences in 

plasma cocaine levels and subjective effects after acute 

cocaine administration in human volunteers. 

Psychopharmacology 125:346–354, 1996. 
Research Findings

141

Inner-City Cocaine Abusers in Baltimore Respond to VoucherBased Treatment

By Michael D. Mueller, NIDA NOTES Contributing Writer 

Volume 10, Number 5 (September/October, 1995)

Although reports on voucher-based treatment of cocaine 

abuse are encouraging, most of the research to date has 

been carried out on white males in Vermont, a largely 

rural State. The question on the minds of drug abuse 

researchers in metropolitan areas has been, “How well 

does it work with inner-city cocaine abusers?” 

In Baltimore, Dr. Kenneth Silverman of Johns Hopkins 

University, Dr. Kenzie Preston of NIDA’s Division of 

Intramural Research (DIR), and their colleagues tested the 

voucher-based treatment of cocaine abuse on an especially 

challenging population: injecting heroin abusers in methadone treatment with a history of heavy cocaine abuse. 

The voucher-based strategy produced impressive results. 

“The vouchers are powerful reinforcers, even among 

inner-city patients dependent on more than one drug,” 

says Dr. Silverman. “When the vouchers are tied to 

cocaine-free urine, they help patients stay off cocaine for 

many weeks or months at a time.” 

“Moreover, cocaine abusers often report a loss of control over their ability to not use the drug,” explains Dr. 

Silverman. “The vouchers are a reward for not using 

cocaine. And rewards—even relatively small ones—can be 

strong motivators.” 

The Baltimore study involved 37 patients randomly 

assigned to two groups. Both groups received standard 

counseling for methadone treatment, but they differed in 

how vouchers were made available to patients. 

Patients in Group A received a voucher for each cocainefree urine sample, with samples collected three times a week 

over 12 weeks. The value of the voucher increased with the 

number of consecutive cocaine-free urine specimens. 

Each patient in Group B was “yoked” to a patient in 

Group A. That is, Group B patients also received vouchers matched in pattern and value to those earned by their 

counterparts in Group A. However, Group B vouchers 

were not tied to the outcome of urine tests. Group B 

patients were told that they would receive vouchers in an 

unpredictable manner and that the vouchers could be used 

to help them stop using cocaine by purchasing goods and 

services that promote a healthy lifestyle. 

Dr. Silverman found that the treatment worked when the 

voucher was tied to a cocaine-free urine sample. Patients 

given vouchers for clean urines stayed off cocaine for more 

weeks and for longer stretches of time. Nearly half of the 

patients in Group A stayed off cocaine for continuous 

periods ranging from 7 to 12 weeks. 

In contrast, only one patient in Group B was able to 

string together more than 2 cocaine-free weeks. The differences between the two groups were both clinically and 

statistically significant. 

“The study design made it clear that the strength of the 

voucher is in the link to cocaine-free urine,” says Dr. 

Silverman, “and not in the monetary value of the vouchers 

or the access they give to community services. They work 

because they reinforce a particular behavior—not using 

cocaine.” 

The drop in cocaine use was not offset by an increase in 

the use of alcohol or other drugs. Researchers found slight 

decreases in the use of opiates and alcohol. 

“These results are very encouraging,” says Dr. Silverman. 

“We must find more effective ways to treat cocaine abuse. 

Further, cocaine abuse is often intertwined with other 

drug addictions. It’s a common problem in methadone 

treatment programs.” 

However, he is cautiously optimistic. “There’s a lot to 

learn about this voucher-based approach. We need to see 

how it works over longer periods of time and find out 

why it doesn’t work for some cocaine abusers.

“Still,” says Dr. Silverman, “the short-term effectiveness 

of this approach is good news. We may be able to extend 

abstinence through continued reinforcement. And, as 

others have observed, keeping cocaine abusers off cocaine 

for even short periods of time may provide windows of 

opportunity for other treatments to take hold and start 

working.” 

Dr. Preston, principal investigator for the study, says that 

researchers also are interested in exploring how well 

Patients given vouchers for clean urines 

stayed off cocaine for more weeks 

and for longer stretches of time than 

patients whose vouchers were not tied 

to the outcome of urine tests.
142

contingency management strategies such as the voucherbased approach work when joined with medical treatment. 

“It’s possible,” says Dr. Preston, “that the most effective 

treatment for cocaine abuse will be in the combination of 

contingency management with medication.” 

Sources 

• Silverman, K.; Brooner, R.K.; Montoya, I.D.; 

Schuster, C.R.; and Preston, K.L. Differential 

reinforcement of sustained cocaine abstinence in 

intravenous polydrug abusers. In: Harris, L.S., ed. 

Problems of Drug Dependence 1994: Proceedings of 

the 56th Annual Scientific Meeting, The College on

Problems of Drug Dependence, Inc. NIDA Research 

Monograph No. 153. NIH Pub. No. 95–3883. 

Washington, D.C.: Supt. of Docs., U.S. Govt. Print. 

Off., 1995, p. 212. 

• Silverman, K.; Wong, C.J.; Umbricht-Schneiter, A.; 

Montoya, I.D.; Schuster, C.R.; and Preston, K.L. 

Voucher-based reinforcement of cocaine abstinence: 

effects of reinforcement schedule. In: Harris, L.S., ed. 

Problems of Drug Dependence 1995: Proceedings of the 

57th Annual Scientific Meeting, The College on

Problems of Drug Dependence, Inc. NIDA Research 

Monograph No. 162. Washington, DC: Supt. of 

Docs., U.S. Govt. Print. Off., 1996, p. 97. 
143

Research Findings

Voucher System Is Effective Tool in Treating Cocaine Abuse

By Michael D. Mueller, NIDA NOTES Contributing Writer 

Volume 10, Number 5 (September/October, 1995)

One of the biggest challenges in treating cocaine abuse is 

getting cocaine abusers to stay in treatment long enough 

to take the first difficult steps toward recovery. However, 

the voucher-based approach developed by Dr. Stephen T. 

Higgins and colleagues at the University of Vermont may 

help cocaine abusers take those vital first steps. 

“This voucher-based strategy that has come out of 

Vermont represents important progress,” says Dr. John J. 

Boren, the NIDA program officer overseeing this research. 

“The vouchers help hold cocaine abusers in treatment.” 

The Higgins approach allows cocaine abusers to build up 

points during outpatient treatment. The points, earned 

with urine specimens that test negative for cocaine, are 

recorded on vouchers, which can be exchanged for items 

that promote healthy living. These items include YMCA 

passes and continuing education materials. 

“Cocaine abusers never receive cash-only vouchers,” emphasizes Dr. Higgins. “The patients and counselors must agree 

on the items to be purchased with the vouchers.” 

Urine specimens are collected three times a week, and the 

vouchers increase in value the longer the person stays off 

cocaine. Patients receive bonus vouchers at the end of the 

week if all three urine specimens have tested negative. 

Cocaine is highly addictive; 1 to 2 million Americans are 

dependent on it. Up to 80 percent of cocaine abusers drop 

out of treatment programs, according to Dr. Higgins. 

Further, Dr. Higgins points out, “The demand for 

cocaine abuse treatment is so large, and the environmental 

influence of the addiction process so powerful, that we 

must find ways to help cocaine abusers on an outpatient 

basis. Sure, we can treat them in the hospital, but then 

they return to their home communities, where they face 

old influences, often without alternatives and skills to 

withstand the lure of cocaine.”

The voucher-based system creates an alternative, builds 

coping skills, and strengthens social relationships. The 

approach involves more than regular urine tests and 

vouchers for points. It also includes intensive counseling 

directed at employment, recreation, relationships, skills 

training, and structuring the day. Family and friends are 

brought into the counseling process. Patients who are 

alcohol dependent are also given Antabuse therapy to 

treat their dependence. 

Thus, the Higgins approach to treating cocaine dependence focuses on behavior, creating paths for behavior 

change, rewarding positive change, and strengthening 

social relationships that reinforce healthy choices. The 

treatment package has several parts, but the voucher piece 

seems particularly strong, notes Dr. Higgins. 

To many, stacking vouchers against cocaine addiction is 

like pitting David against Goliath. However, like David, the 

vouchers have proven to be more effective than expected. 

“It surprises many people that a stack of paper can outweigh the powerful urge to use cocaine,” says Dr. Higgins. 

“But it makes sense in terms of what we know about why 

people use drugs. Also, cocaine users reach a point where 

they want help.” 

The key to the success of the vouchers is that they have a 

“reinforcing effect” that competes with the one produced 

by cocaine use. They are an alternative that is available 

immediately, but only if cocaine is not used. This is the 

heart of the theory that drives the treatment strategy. 

Cocaine produces powerful reinforcing effects. When 

cocaine abusers use cocaine, the drug acts directly on particular areas of the central nervous system, which makes 

the user want to use cocaine again, often producing cycles 

of intensive, repeated use or “binges.” 

Dr. Stephen Higgins (right) gives a patient a voucher that can be

exchanged for items that promote healthy living. The voucher, similar 

to the one shown on the following page, is earned with urine 

specimens that test negative for cocaine.
144

The voucher, on the other hand, is reinforcement for not 

taking cocaine. Although the dollar value of the voucher 

may not be great, the value of this alternative, immediate 

reinforcer can be quite high. 

“Many areas of research support the concept of alternative reinforcement as important to preventing and treating 

drug abuse,” observes Dr. Higgins. “Quite simply, reinforcement is a basic principle of human behavior. When 

we’re discussing cocaine use, we’re talking about behavior 

that is very sensitive to its consequences.” 

Cocaine abuse is not guided by a moral compass or free 

will. The drug acts on “reward centers” in the brain. 

Further, some researchers believe that the effects of 

cocaine on these reward centers are just as powerful as the 

effects of food and sex, notes Dr. Higgins. 

Dr. Higgins and his colleagues are searching for ways to 

apply these principles of behavioral pharmacology to drug 

abuse treatment. 

Dr. Higgins is quick to point out that, “Though cocaine 

is a powerful reinforcer, its use is context-dependent. 

Usually, the lifestyles of cocaine abusers are in such a state 

that their natural reinforcers for healthy behavior are in 

disarray or not available. 

“Cocaine abusers, and especially ‘crack’ abusers, often 

come from deprived environments,” he says. “Many times, 

those neighborhoods provide an almost ideal environment 

for cocaine to exert its powerful reinforcing effects. There 

are few prosocial alternatives. 

“We need to work toward creating environments in which 

those reinforcing effects are less powerful—in which people have positive, drug-free alternatives.” 

Dr. Higgins and his colleagues began researching the 

voucher-based strategy in 1990. First, they compared the 

behavior-change package to a more traditional outpatient 

counseling program in a study of 28 cocaine abusers over 

a 12-week period. The more traditional program operates 

on the premise that cocaine abuse is a treatable disease; it 

includes counseling, lectures, videotape presentations, 

self-help sessions, and working with a sponsor. 

Eleven of the 13 patients assigned to the behavior change 

program completed 12 weeks of treatment, compared 

to 5 of the 15 patients in the traditional program. The 

researchers found that patients in behavioral treatment 

had significantly longer periods with cocaine-free urine. 

The findings were much the same for a subsequent study 

of 38 patients over 24 weeks. 

Next, Dr. Higgins narrowed his research to the voucher 

part of the treatment program. He found that 90 percent 

in the voucher group completed a 12-week treatment program, compared to 65 percent in the no-voucher group. 

Over 24 weeks, 75 percent in the voucher group, versus 

40 percent in the no-voucher group, completed treatment. When it came to continuous cocaine abstinence, 

the voucher group averaged 11.7 weeks; the no-voucher 

group, 6 weeks. 

Recently, the researchers reported on a followup of 

patients who took part in the 24-week study. Cocaine use 

was evaluated 3 months and 6 months after the completion of the 24-week program. Again, the voucher-based 

behavioral package produced significantly greater cocaine 

abstinence than the more traditional approach. 

Although the findings are encouraging, Dr. Higgins and 

others caution that most research to date has been on 

white males in Vermont, a rural State. Further studies are 

needed to determine the effectiveness of the vouchers over 

longer periods of time and among women, urban populations, and other cultural groups. 

Dr. Higgins’ research results are supported by those of 

Dr. Kenzie Preston of NIDA’s Division of Intramural 

Research, Dr. Kenneth Silverman of Johns Hopkins 

University, and their colleagues, who found that the 

voucher system seems effective in treating inner-city 

cocaine abusers. 

“An immediate application of the voucher approach—which 

has demonstrated its short-term effectiveness—might 

be to reduce cocaine abuse among pregnant women,” 

suggests Dr. Higgins. The voucher-based intervention 

could lead to healthier newborns. It would also be costeffective, as neonatal intensive care units are extremely 

expensive, he says. 

Some observers question the acceptability of “paying” 

cocaine abusers not to use cocaine. In answer, Dr. Higgins 

says, “We don’t view it as paying them to do the right 

thing. No cash changes hands. We are finding ways to 

provide alternative positive reinforcement. We combine 

the vouchers with behavioral therapy so that when the 

vouchers are gone, the individual can then find support for a cocaine-free lifestyle among his or her natural 

resources.” 

Dr. Higgins’ academic training dovetails with what 

he learned about drug abuse during his youth in 

Philadelphia. “I grew up around a lot of drug abuse. What 

I saw on the streets agrees with the scientific studies that 

This voucher certifies that ————––––––––––––––––––

has received ————–––––– points today, to equal 

a total of ————–––––– points to date.

Date ———— Staff Signature:————––––––––––––––– 
145

tell us that there are things we should be doing to give 

young people alternatives to cocaine,” he says. 

“We need to look for forms of alternative reinforcement 

or incentive programs that can be used in community 

settings,” he continues. “Perhaps local merchants would 

be willing to contribute goods and services. Access to 

sports facilities and coaches are examples of healthy alternatives. We need to think creatively.” 

Sources 

• Higgins, S.T.; Delaney, D.D.; Budney, A.J.; Bickel, 

W.K.; Hughes, J.R.; Foerg, F.; and Fenwick, J.W. 

A behavioral approach to achieving initial cocaine 

abstinence. American Journal of Psychiatry

148(9):1218–1224, 1991. 

• Higgins, S.T.; Budney, A.J.; Bickel, W.K.; Hughes, 

J.R.; Foerg, F.; and Badger, G. Achieving cocaine 

abstinence with a behavioral approach. American 

Journal of Psychiatry 150(5):763–769, 1993. 

• Higgins, S.T.; Budney, A.J.; Bickel, W.K.; Foerg, F.; 

Donham, R.; and Badger, G.J. Incentives improve 

outcome in outpatient behavioral treatment of 

cocaine dependence. Archives of General Psychiatry 

51:568–576, 1994. 

• National Institute on Drug Abuse. Director’s Report to 

the National Advisory Council on Drug Abuse. 

Rockville, MD: NIDA, 1995. From NIDA NOTES, 

September/October, 1995. 
Research Findings

146

NIDA-Supported Scientists Identify Receptor Associated with 

Cocaine Abuse

By John A. Bowersox, NIDA NOTES Contributing Writer 

Volume 10, Number 5 (September/October, 1995) 

Much of NIDA’s cocaine treatment medication research 

is directed toward finding compounds that counteract the 

specific changes that cocaine causes in the brain. Scientists 

know that cocaine affects the brain’s dopaminergic 

pathways—areas that use the chemical dopamine to transmit messages between brain cells. They have found that 

cocaine prevents the reuptake, or retrieval, of dopamine 

by the brain cells that release it. The resulting flood of 

dopamine overstimulates the receptor molecules to which 

dopamine binds, an effect that scientists believe may 

account, in part, for cocaine’s addictive effects. 

Over the last few years, researchers have identified several kinds of dopamine receptors, each possessing distinct 

molecular properties and having different anatomical 

distributions within the brain. Scientists hope to identify 

potential targets for new cocaine treatment medications by 

determining whether some types of dopamine receptors 

play a larger role than others in producing cocaine’s addictive effects. 

NIDA-funded researchers at The Scripps Research 

Institute in La Jolla, California, have reported that one 

of these receptors, known as D-3, looks particularly promising as a target for cocaine treatment medication development. 

“It looks like a pretty good bet,” says Scripps researcher Dr. 

George F. Koob about the D-3 receptor’s potential as a target for cocaine therapies. In animal experiments, Dr. Koob 

and Dr. S. Barak Caine found that the D-3 dopamine 

receptor appears to be a central factor in cocaine use. 

The researchers reported that rats that had access to 

cocaine on a daily basis took less of the drug when given 

compounds that selectively bind to D-3 receptors. The 

rats in the study were trained to self-administer a cocaine 

solution intravenously. After baseline rates of cocaine use 

were established, the researchers added various dopamine 

agonists, compounds that bind to and stimulate dopamine 

receptors, to the rats’ cocaine source. 

Drs. Koob and Caine found that agonists with high 

affinities for D-3 receptors reduced cocaine intake more 

effectively than did agonists with low affinities for D-3 

receptors. In fact, the higher an agonist’s affinity for the 

D-3 receptor, the more effective it was at reducing cocaine 

self-administration. 

The researchers hypothesize that D-3-selective agonists may 

reduce cocaine intake by enhancing cocaine’s reinforcing 

properties. In this view, the rats took less cocaine because, 

when combined with the D-3 agonists, a smaller dose of 

cocaine felt the same as their “regular” dose. They believe, 

however, that much remains to be learned about the role 

that the D-3 receptor plays in cocaine reinforcement. 

The researchers also examined whether the rats would selfadminister the D-3 agonists in the absence of cocaine—a 

step necessary to determine the agonists’ abuse potential. 

Ideally, therapies for drug abuse should have little or no 

abuse liability. They found that the rats self-administered 

only very high doses of the high-affinity D-3 agonists—

the doses of these compounds that reduced cocaine intake 

were not self-administered. This is important, says Dr. 

Koob, because it suggests that, at therapeutic levels, D-3 

agonists would have low potential for abuse. 

NIDA officials say that they are encouraged by Dr. Koob’s 

findings. “We’re excited about his work, and we’re hoping 

to follow it up in the context of our preclinical cocaine 

treatment discovery testing program,” says Dr. Carol 

Hubner of NIDA’s Medications Development Division 

(MDD). Dr. Hubner notes that some of the compounds 

that Dr. Koob studied have entered MDD’s preclinical 

drug discovery program. 

Dr. Koob reports that new research from his laboratory, 

done in collaboration with Drs. Jean-Charles Schwartz and 

Pierre Sokoloff in Paris, and Dr. Larry Parsons, a NIDA 

postdoctoral fellow, confirms these earlier findings. “We 

have tested new agonists that are even more selective for 

the D-3 receptor and have observed an even greater reduction of cocaine intake in rats,” he says. He adds that his 

new research also has defined more precisely the area of the 

brain at which the D-3 receptor mediates cocaine abuse. 

“We believe that the site of action of the D-3 receptor is 

localized to the shell of the nucleus accumbens,” he says. The 

D-3 receptor’s localization to this structure, which lies on the 

underside of the midbrain, has important implications for 

cocaine treatment medication development, he says. 

Because D-3 receptors are concentrated in an area of 

the brain associated with emotional and endocrine functions and not in areas that regulate motor functions, he 

says, therapies targeted at D-3 receptors specifically may 
147

reduce cocaine intake without producing motor side 

effects. Other medications that target dopamine receptors nonspecifically have been shown to cause side effects 

that are similar to the movement disorders associated with 

Parkinson’s disease.

“We don’t expect that there would be any Parkinsonian 

side effects with medications that specifically target the 

D-3 receptor,” says Dr. Koob. 

Sources 

• Caine, S.B., and Koob, G.F. Modulation of cocaine 

self-administration in the rat through D-3 dopamine 

receptors. Science 260:1814–1816, 1993. 

• Caine, S.B., and Koob, G.F. Pretreatment with the 

dopamine agonist 7-OH-DPAT shifts the cocaine 

self-administration dose-effect function to the left 

under different schedules in the rat. Behavioral 

Pharmacology 6:333–347, 1995. 
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