Biological Components of Substance Abuse

and Addiction

September 1993

OTA-BP-BBS-117

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GPO stock #052-003-01350-9
Recommended Citation:

U.S. Congress, Mice of Technology Assessment, BioZogicaZ Components of

Substance Abuse and Addiction, OTA-BP-BBS-1 17 (Washington, DC: U.S.

Government printing Offke, September 1993).

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ISBN 0-16 -042096- 2
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Foreword

ubstance abuse and addiction are complex phenomena that defy simple

explanation or description. A tangled interaction of factors contributes to

an individual’s experimentation with, use, and perhaps subsequent abuse

of drugs. Regardless of the mix of contributing factors, the actions and

effects exerted by drugs of abuse underlie all substance abuse and addiction. In

order to understand substance abuse and addiction it is first necessary to

understand how drugs work in the brain, why certain drugs have the potential

for being abused, and what, if any, biological differences exist among

individuals in their susceptibility to abuse drugs.

This background paper is the first of two documents being produced by

OTA as part of an assessment of Technologies for Understanding the Root

Causes of Substance Abuse and Addiction. The assessment was requested by the

House Committee on Government Operations, the Senate Committee on

Governmental Affairs, and the Senate Committee on Labor and Human

Resources. This background paper describes biological contributing factors to

substance abuse and addiction. The second document being produced by this

study will discuss the complex interactions of biochemical, physiological,

psychological, and sociological factors leading to substance abuse and

addiction.

OTA gratefully acknowledges the generous help of the Advisory Panel,

contributors, and reviewers who gave their time to this project. OTA, however,

remains solely responsible for the contents of this background paper.

a“+- -

Roger C. Herdman, Director

iii
Advisory Panel

Patricia Evans

Chair

Bayview-Hunter’s Point

Foundation

San Francisco, CA

Marilyn Agulrre-Mollna

Robert Wood Johnson Medical

School

Piscataway, NJ

Jeffrey G. Becker

The Beer Institute

Washington, DC

Lawrence S. Brown, Jr.

Addiction Research and

Treatment Corp.

Brooklyn, NY

Mary Edwards

Camden House

Detroit, Ml

Bernard Ellis, Jr.

New Mexico Department of

Health

Santa Fe, NM

Robbie M. Jackman

State of Tennessee

Department of Public Health

Nashville, TN

Sheppard Kellam

School of Hygiene and

Public Health

The Johns Hopkins University

Baltimore, MD

Herbert Kleber

College of Physicians and

surgeons

Columbia University

New York NY

George Koob

Department of Neuropharmacology

The Scripps Research Institute

La Jolla, CA

Mary Jeanne Kreek

Department of Biology and

Addictive Diseases

The Rockefeller University

New York, NY

John Lucas

John Lucas Enterprises

Houston, TX

Spero Manson

University Health Science Center

Colorado Psychiatric Hospital

Denver, CO

Roger Meyer

David F. Musto

Child Studies Center

Yale University

New Haven, CT

Ruben Ortega

Ruben Ortega Associates

Phoenix, AZ

Sue Rusche

National Families in Action

Atlanta, GA

Lawrence Wallack

School of Public Health

University of California Berkeley

Berkeley, CA

Kenneth E. Warner

School of Public Health

University of Michigan

Ann Arbor, MI

Roger W. Wilkins

Robinson Professor of History and

American Culture

George Mason University

Fairfax, VA

Department of Psychiatry

University of Connecticut

Farmington, CT

NOTE: OTA apprecutes and is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel members. The panel

does not, however, necessarily approve, “disapprove, or endorse this report. OTA assumes full responsibility for the report and the accuracy of its

contents.

iv
Clyde Behney

Assistant Director

Health, Life Sciences

and the Environment

Michael Gough

Program Manager

Biological and Behavioral Sciences

Program

PRIMARY CONTRACTOR

David R. Liskowsky

Arlington, VA

Kevin W. O’Connor

Project Director

Jennifer Schmidt

Analyst

Thomas R. Vischi

OTA Fellow

Ellen McDermott

Research Assistant

CONTRACTORS

Carter Blakey

Editor

Bethesda, MD

Preject Staff

Theodore J. Cicero

Washington University School of

Medicine

Stephen Dinwiddie

Washington University School of

Medicine

William J. McBride

IndianaUniversity School of

Medicine

ADMINISTRATIVE STAFF

Cecile Parker

Office Administrator

Linda Rayford-Journiette

PC! Specialist

Jene Lewis

Administrative Secretary

Theodore Reich

Washington University School of

Medicine
contents

1

2

3

4

Executive Summary 1

Drug Action 2

Genetic Factors 6

Role of Learining 7

Basic Concepts 9

The Brain Reward System 10

Neuroadaptive Responses 11

Abuse Liability 13

Role of Learning 15

Chapter 2 References 16

The Neuropharmacology of Drugs of Abuse 19

Neurophannacology 20

Drugs of Abuse 21

summary 35

Chapter 3 References 36

Genetics 39

Do Inherited Factors Exist? 40

What Is Inherited? 43

Summary 50

Chapter 4 References 51

APPENDIXES

A The Drug Evacuation Committee of the College on

Problems of Drug Dependence 59

B Acknowledgments 61

VI
s

ubstance abuse and addiction are complex phenomena

that defy simple explanation or description. A tangled

interaction of factors contributes to an individual’s

seeking out, using, and perhaps subsequently abusing

drugs. Since more individuals experiment with drugs than

eventually develop substance abuse problems, great interest

persists in understanding what differentiates these groups.

Factors that can play a role in drug abuse susceptibility include

a person psychological makeup (e.g., self-esteem, propensity to

take risks, irnpulsivity, depression), biological response to drugs

and environmental situation (e.g., peer groups, family organization, socioeconomic status), and the availability of drugs. The

exact combination of elements that leads to substance abuse and

addiction varies among individuals.

Regardless of the mix of contributing factors, the actions and

effects that drugs of abuse exert underlie all substance abuse and

addiction. In order to understand substance abuse and addiction

one must first understand how drugs work in the brain, why

certain drugs have the potential for abuse, and what, if any,

biological differences exist among individuals in their susceptibility to abuse drugs. While numerous factors ultimately

contribute to an individual’s drug-taking behavior, understanding the biological components is crucial to a better comprehension of substance abuse and addiction. In this background paper,

the Office of Technology Assessment (OTA) describes the

biological components of substance abuse and addiction.

Two biological factors contribute to substance abuse and

addiction: the effects drugs of abuse exert on the individual, and

the biological status of the individual taking drugs. The former

Executive

Summary 1

w

1
2 I Biological Components of Substance Abuse and Addiction

Box l-A–Neuropharmacology

Neurons are the cells that process information in the brain. Neurotransmitters are chemicals released by

neurons to communicate with other neurons. When a neuron is activated it releases a neurotransmitter into the

synapse, the gap between two neurons (figure l-l). The molecules of the neurotransmitter move across the

synapse and attach, or bind, to proteins called receptors in the outer membrane of an adjacent ceil. Once a

neurotransmitter activates a receptor, it unbinds from the receptor and is removed from the synapse. This is done

either by the neurotransmitter being taken backup into the neuron that released it or by its being chemically broken

down.

For each neurotransmitter in the brain, there are several specific receptors to which it can attach. Binding by

the neurotransmitter activates the receptor. Receptors can be linked to a variety of membrane and cellular

mechanisms that are turned on or off by the activation of the receptor. while receptors are specific for a

neurotransmitter, there maybe a variety of receptor subtypes, linked to different cellular mechanisms and to

different neuronal circuits, that all respond to the same neurotransmitter. In this way one neurotransmitter can have

diverse effects indifferent areas of the brain. Many chemicals have been identified as neurotransmitters. Sores

are of particular relevance to the rewarding properties of drugs of abuse. These include dopamine, norepinephrine,

serotonin, opioids and other neuropeptides, gamma amino butyric add (GABA), and glutamate.

A neuron can have thousands of receptors for many different neurotransmitters. Some neurotransmitters

activate neurons (excitatory neurotransmitters), while others decrease neuron activity (inhibitory neurotransmitters). Sometimes a receptor for one neurotransmitter can affect a receptor for another neurotransmitter. In such

cases, the receptors are biochemically coupled: the activation of one modulates the function of the other, either

increasing or decreasing its activity. A neuron can also have receptors for the neurotransmitter it releases. Such

receptors are acted on by the neuron’s own neurotransmitter to regulate the release of the neurotransmitter. Thus,

these so-called autoreceptors act as a feedback mechanism to regulate a neuron’s activity. The activity ofa neuron

will be determined by the cumulative activity of all of its various receptors.

Drugs that work in the brain, including drugs of abuse, alter normal neuropharmacological activity through

a varietyofdifferent mechanisms. They can affect the production, release, or reuptake of a neurotransmitter, they

can mimic or block the action of a neurotransmitter at a receptor, or they can interfere with or enhance the activity

of a membrane or cellular mechanism associated with a receptor. Prolonged drug use has the potential to alter

each of these processes.

SOURCE: office of Technology Assessment, 1993.

relates to the acute mechanisms of action of drugs drugs is that most of these drugs act, at least in

of abuse in the brain and the long-term effects that

occur after chronic exposure. The latter pertains

to an individual’s biological constitution, most

importantly the presence of inherited characteristics, which affects that person’s response to a

drug.

DRUG ACTION

I Acute Actions

Drugs of abuse alter the brain’s normal balance

and level of biochemical activity (box l-A). What

separates drugs of abuse from other psychoactive

part, on those areas of the brain that mediate

feelings of pleasure and reward (box l-B).

The ability to induce activity in the so-called

brain reward systems gives drugs of abuse positive reinforcing actions that provoke and support

their continued use and abuse. Reinforcement is

defined as the likelihood that the consequences of

taking the drug will increase the behavior directed

toward seeking that drug. Put more simply,

individuals who use drugs experience some

effect, such as pleasure, detachment, or relief

from distress, that initially establishes and then

maintains drug self-administration. The con-
Chapter l—Executive Summary | 3

Figure l-l—The Synapse and

Associated Structures

T T

Neurotransmitters Receptors

Receiving cell

SOURCE: Office of Technology Assessment, 1993.

sequence of taking the drug enhances the prospect

that it will continue to be used for some real or

perceived effect and eventually compulsive selfadministration. In fact, the capacity of a drug to

support self-administration in experimental animals is a measure of the drug’s strength as a

reinforcer.

While growing evidence indicates that the

brain reward system likely plays a role in the

reinforcing properties of most drugs of abuse, the

precise mechanisms involved in all drugs of abuse

have yet to be completely described. The rewarding properties of stimulant drugs such as cocaine

and amphetamines are due to a direct increase in

the activity of the neurotransmitter dopamine in

the mesocorticolimbic dopamine pathway (see

box l-B). Opiates, on the other hand, indirectly

stimulate dopamine activity by activating other

neurotransmitter pathways, which in turn increase

dop amine activity in the mesocorticolimbic pathway (MCLP). Similarly, alcohol, barbiturates,

and benzodiazepines also indirectly activate MCLP.

All of these drugs have strong reinforcing properties. Phencyclidine (PCP) is also a strong reinforcer but its relationship, if any, to activity in

MCLP has not been established. Other drugs are

either weak reinforcers or have not been shown to

support self-administration in animal experiments. Nicotine activates dopamine neurons in

the mesocorticolimbic system. However, when

compared with cocaine or amphetamine, this 

effect is modest. Likewise, caffeine is a weak

reinforcer, but the precise mechanisms of its

reinforcement are unclear. Finally, while cannabis and lysergic acid diethylamide (LSD) produce

positive effects that clearly support their use,

there is currently little empirical evidence that

they act as reinforcers in controlled experiments.

# Chronic Actions

Changes occur in the brain when it is exposed

to drugs. Beyond their immediate, rewarding

properties, drugs of abuse, when used on a

chronic, long-term basis, can cause either permanent changes in the brain or alterations that may

take hours, days, months, even years to reverse on

drug cessation. These changes are adaptive responses related to the pharmacological action of

a given drug that occur in the brain to counter the

immediate effects of a drug.

Tolerance develops to a drug when, following

a prolonged period of use, more of the drug is

required to produce a given effect. Tolerance

occurs with many types of drugs and is a common,

but not necessary, characteristic of drugs of

abuse. Tolerance can contribute to drug-taking

behavior by requiring that an individual take

progressively larger doses of a drug to achieve a

desired effect.

Dependence occurs when, with prolonged use

of a drug, neurons in the brain adapt to the drug’s

presence such that the use of the drug is now

required to maintain normal function in the cells.

On abrupt withdrawal of the drug, the neuron

behaves abnormally and a “withdrawal syndrome” ensues, Generally, the withdrawal syn-
4 I Biological Components of Substance Abuse and Addiction

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drome is characterized by a series of signs and

symptoms that are opposite to those of the acute

effects of the drug. Withdrawal creates a craving

or desire for the drug and plays a very strong role

in recurrent patterns of relapse, in maintaining

drug-seeking behavior to forestall the withdrawal

syndrome, and in the need to reestablish some

sense of normalcy.

Sensitization occurs when the effects of a given

dose of a drug increase after repeated administration. Thus, sensitization is the opposite of tolerance. Sensitization to a drug’s behavioral effects

could play a significant role in supporting drugtaking behavior.

For example, while tolerance to some of the

effects of cocaine and amphetamines develops,

sensitization to other of their effects can also

occur. Also, while it is unclear horn available data

whether tolerance develops to cocaine’s reinforcing effects, the notion is supported by some

experimental evidence and anecdotal reports

born cocaine users that the drug’s euphoric

actions diminish with repeated use. Tolerance

also develops to the effects, including the reinforcing properties, of opiates and alcohol.

A withdrawal syndrome of varying severity is

associated with most drugs of abuse. Barbiturates,

alcohol, stimulants, opiates, and benzodiazepines

produce pronounced and sometimes severe withdrawal symptoms, while those for nicotine and

caffeine are less intense. A mild withdrawal is

associated with cannabis use, while there is no

evidence of a withdrawal syndrome related to

LSD.

I Abuse Liability

The abuse liability of a drug is a measure of the

likelihood that its use will result in drug addiction. Many factors ultimately play a role in an

individual’s drug-taking behavior; nevertheless,

the abuse potential of a drug is related to its

intrinsic rewarding properties and/or the neu-
Chapter l–Executive Summary | 5

roadaptive responses that result from its prolonged use. Drugs can be tested and screened for

their abuse liability using animals as models. The

criteria that can be evaluated to classify a drug as

having significant abuse potential are pharmacological equivalence to known drugs of abuse,

demonstration of reinforcing effects, tolerance,

and physical dependence. The capacity to produce reinforcing effects is essential to any drug

with significant abuse potential, whereas tolerance and physical dependence most commonly

occur but are not absolutely required to make such

a determination.

SELF-ADMINISTRATION

The predominant feature of all drugs with

significant abuse potential properties is that they

are self-administered. In fact, self-administration

of a drug to the point when the behavior becomes

obsessive and detrimental to the individual is the

primary criterion that must be met to classify a

drug as having significant potential for addiction.

In addition to self-administration, another contributing factor to abuse liability is the notion of

craving and the tendency of individuals to relapse

to drug use during withdrawal. Although craving

is a difficult term to quantify, once a drug is

voluntarily or involuntarily withdrawn, the desire

to take the drug can play a role in the relapse to

substance abuse.

Animals can be readily trained to selfadminister drugs. Animal models of selfadministration provide a powerful tool that can

give a good indication of the abuse liability of

new or unknown drugs. These models also permit

an examination of the behavioral, physiological,

and biological factors that lead to sustained

self-administration.

DRUG DISCRIMINATION

Another tool in the assessment of abuse liability of drugs is drug discrimination, which refers to

the perception of the effects of drugs. Specifically, animals or humans trained to discriminate

Figure 1-2—The Mesocortlcolimbic Pathway

Ventral\

tegmental v

area

The mesocorticolimbic pathway from the ventral tegmental

area to the nucleus accumbens and the frontal cortex is a key

component of the brain reward system for drug reinforcement.

SOURCE: Office of Technology Assessment, 1993 .

a drug from a placebo show a remarkable ability

to distinguish that drug from other drugs with

different properties. These procedures also permit

a determination of whether the subject considers

the drug to be the pharmacological equivalent of

another drug. Pharmacological equivalence refers

to the fact that drugs of a particular class, such as

opiates, stimulants, and depressants, cause a

series of effects on the brain and other organs that

collectively constitute their pharmacological profile.

DEPENDENCE AND TOLERANCE

Dependence and tolerance can readily be

induced in animals by chronic administration of

drugs. Following abrupt withholding of a drug, a

withdrawal syndrome will often develop and the

motivation for self-administration of the drug

may be increased. Thus, the capacity of a drug to

induce neuroadaptive motivational changes can

be assessed. Furthermore, since the understanding of the neuroadaptive changes that take place

during the development of physical dependence

and tolerance are poorly understood in humans,

animal models offer a unique opportunity to carry

out experiments designed to address these issues.
6 | Biological Components of Substance Abuse and Addiction

GENETIC FACTORS

Progress in understanding the genetics of

various conditions and diseases has brought with

it a realization that substance abuse and addiction

probably involve a genetic component. That is,

hereditary biological differences make some individuals either more or less susceptible to drug

dependency than others. While it seems likely

that inherited differences exist, a genetic component alone is insufficient to produce substance

abuse and addiction.

Unlike disorders, such as Huntington’s disease

and cystic fibrosis, that result from the presence

of alternations in a single gene, a genetic component of substance abuse is likely to involve

multiple genes that control various aspects of the

biological response to drugs or physiological

predisposition to become an abuser. In addition,

the complex nature of drug dependency, involving many behavioral and environmental factors,

indicates that any genetic component acts in

consort with other nongenetic risk factors to

contribute to the development of substance abuse

and addiction. Thus, the presence of a genetic

factor does not ensure drug addiction nor does its

absence guarantee protection from drug addiction.

Two questions arise when considering a genetic component to substance abuse and addiction: Do inherited factors exist? And, if so, what

are they? To date, much of the work done in this

field relates to alcoholism. Less is known about

the genetic aspects of the abuse of other drugs.

I Do Inherited Factors Exist?

Results from family studies, twin studies, and

adoption studies as well as extensive research on

animal models indicate that heredity influences

normal as well as pathological use of alcohol.

Animal studies have established that genetic

factors contribute to alcohol preference, the

reinforcing actions of alcohol, alcohol tolerance,

and alcohol physical dependence. While few

studies have examined the genetic component of

vulnerability to the addictive properties of other

drugs of abuse, evidence from animal studies

confirms the role of a genetic influence on the use

and abuse of drugs other than alcohol. The study

of nonalcoholic drug abuse in humans has been

difficult due to substantially lower population

prevalence and differences in availability and,

hence, exposure to these agents. Investigation in

this area is further hampered by the complexity of

subjects’ drug use: most drug abusers have used

multiple agents. This has led researchers either to

concentrate on one class of drug or to treat all

illicit drug use as equivalent. The tendency to

lump all illicit drugs into one category makes

results difficult to interpret or compare.

I What Is Inherited?

While study results support the role of a genetic

component in alcoholism and probably other drug

abuse, they provide no information about what

exactly is inherited. For example, do individuals

with a family history of drug abuse have an

increased susceptibility or sensitivity to the effects of drugs with reinforcing properties? If a

susceptibility exists, what are its underlying

biological mechanisms? Information about inherited biological mechanisms is most easily derived

from studies of animals bred to have differing

responses to various drugs. However, in humans,

few studies have examined the relationship between inherited behavioral traits and the inherited

biological mechanisms that might underlie them.

In the case of alcohol, studies suggest that low

doses of alcohol are more stimulating and produce a stronger positive reward in rats bred to

have a high preference for alcohol as compared

with normal rats. Experimental data indicate that

this may be due to inherited differences in the

mesocorticolimbic dopamine system (see box

l-B) and an inherited increased response of this

system when exposed to alcohol. Also, alcoholpreferring rats have been found to have different

levels of activity in other neurotransmitter systems that modulate activity in the mesocorti-
Chapter l–Executive Summary | 7

colimbic system. In humans, studies of collegeaged individuals indicate that low initial sensitivity to alcohol may be a predictor for alcoholism

later in life.

Studies using the technique of genetic linkage

analysis 1 have attempted to identify genes that

might be associated with alcoholism in humans.

However, the findings of these studies are inconclusive. While some studies have reported a link

between alcoholism and a gene that regulates the

number of a type of dopamine receptor in the

brain, others have not. The reason for this

discrepancy is unclear, but one study has found a

relationship between the presence of the gene not

only in alcoholism, but also in other disorders

such as autism, attention deficit hyperactivity

disorder, and Tourette’s syndrome. Thus, the

presence of the gene may cause an alteration in

the brain dopamine system that somehow exacerbates or contributes to alcohol abuse, but is not

uniquely specific for alcoholism.

Fewer studies have focused on possible inherited biological mechanisms associated with the

abuse of other drugs. For example, strains of rats

and mice that differ in their sensitivity to the

reinforcing effects of cocaine and in their cocaineseeking behavior have also been observed to have

differences in the number of dopamine-containing neurons and receptors in certain brain areas.

Also, a comparison of one strain of rat that

self-administers drugs of abuse at higher rates

than another strain found that the higher selfadministering strain exhibited differences in the

intracellular mechanisms that control activity in

some of the neurons in the brain reward system as

compared with the low self-administering strain.

Additional studies exploring the role of genes in

drug response are needed to more fully understand the full range of biological factors associated with drug abuse. The recent development of

new and more sensitive techniques to analyze

brain activity and processes will facilitate these

studies.

ROLE OF LEARNING

The learning that occurs when an individual

takes drugs is an important contributing force in

the continued use and craving of drugs. Drugs of

abuse produce positive or pleasurable feelings in

the user and have reinforcing properties. In

addition to these effects, drugs of abuse produce

changes in numerous organ systems such as the

cardiovascular, digestive, and endocrine systems.

Both the behavioral and physiological effects of

a drug occur in the context of an individual’s

drug-seeking and drug-using environment. As a

result, environmental cues are present before and

during an individual’s drug use that are consistently associated with a drug’s behavioral and

physiological effects. With repetition the cues

become conditioned stimuli, that on presentation,

even in the absence of the drug, evoke automatic

changes in organ systems and behavioral sensations that the individual experiences as drug

craving. These associations are difficult to reverse. In theory, repeated presentation of the

environmental cues, absent the drug, should

extinguish the conditioned association. Animal

studies indicate that extinction is difficult to

achieve and does not erase the original learning,

As a result, even once established, the extinction

is readily reversed.

Also, it has long been known that conditioning

occurs in relation to the withdrawal effects of

drugs. This phenomenon, termed conditioned

withdrawal, results from environmental stimuli

acquiring the ability, through classical conditioning, to elicit signs and symptoms of pharmacological withdrawal. The emergence of withdrawal

symptoms as a result of exposure to conditioned

cues can contribute to drug use relapse by

1 Genetic linkage studies establish an association between an area of a specific chromosome and the expression of a trait. Linkage analysis

uses spec~Ic markers that identify the area on a chromosome that might contain the gene of interest. If the marker consistently occurs in

association with the expressed trai~ then it is likely that the gene of interest is in that chromosomal region.
8 I Biological Components of Substance Abuse and Addiction

motivating an individual to seek out and use

drugs.

Thus, exposure to environmental cues associated with drug use in the past can act as a priming

force to motivate voluntary drug-seeking behavior. Drug conditioning can help explain the fact

that many drug abusers often return to environments associated with drug use, even after being

counseled not to. The effects of the environmental

stimuli can be similar to the priming effects of a

low dose of the drug or result in withdrawal

symptoms. In either case these stimuli can occasion further drug use even after successful detoxification.

The complexity of human responses to drugs of

abuse, coupled with the number of drugs that are

abused, complicates understanding of the role of

biology in drug use and abuse. Nevertheless,

scientists know the site of action of many drugs in

the brain, and sophisticated new devices are

expected to improve that understanding. A genetic component to drug use and abuse is likely,

but it has not been fully characterized.
s

imilar to other psychoactive drugs, drugs of abuse alter the

brain’s normal balance and level of biochemical activity.

This can include mimicking the action of naturally

occurring neurotransmitters (chemicals in the brain that

send messages from one nerve cell to another), blocking

neurotransmitter action, or in other ways altering the normal

chemical actions that mediate the transmission of information

within the brain. The ultimate effect is to either elevate or depress

activity in different brain regions (see ch. 3).

What separates drugs of abuse from other psychoactive drugs

is that these drugs act, at least in part, on those areas of the brain

that mediate feelings of pleasure and reward. Inducing activity in

the so-called brain reward system gives drugs of abuse positive

reinforcing actions that provoke and support their continued use

and abuse.

Beyond their immediate, rewarding properties, drugs used on

a chronic, long-term basis can cause either permanent changes in

the brain or alterations that may take hours, days, months, even

years, to reverse on drug cessation. These changes are adaptive

responses that occur in the brain to counter the immediate effects

of a drug. When drug taking is stopped, these changes are often

manifested as effects that are opposite to the initial pleasurable

drug response. The continued administration of drugs to avoid

the aversive effects of drug cessation also contributes to an

individual’s addiction to a drug.

Their immediate and long-term effects imbue drugs of abuse

with reinforcing properties. Reinforcement is defined as the

Basic

Concepts 2

likelihood that the consequences of taking the drug will increase I

the behavior directed toward seeking that drug (6). Put more I
10 I Biological Components of Substance Abuse and Addiction

simply, individuals who use drugs experience

some effect, such as pleasure, detachment, or

relief from distress, that initially establishes and

then maintains drug use. Thus, the consequence

of taking the drug enhances the prospect that it

will continue to be used for some real or perceived

effect and also establishes a need state, hence,

engendering compulsive self-administration.

In addition to their reinforcing effects, drugs of

abuse can have a variety of pharmacological

actions in other areas of the brain and the body.

The ultimate effect of a drug will also be shaped

by other factors including the dose of the drug, the

route of administration, the physiological status

of the user, and the environmental context in

which the drug is taken. The subjective experience of the drug user and his or her overt behavior

is the result of a combination of these factors and

the drug’s pharmacological action.

THE BRAIN REWARD SYSTEM

Eating, drinking,g, sexual, and maternal behav -

iors are activities essential for the survival of the

individual and the species. Natural selection, in

order to ensure that these behaviors occur, has

imbued them with powerful rewarding properties.

The brain reward system evolved to process these

natural reinforcers.

Studies have shown that direct stimulation of

the areas of the brain involved in the reward

system, in the absence of any goal-seeking behavior, produces extreme pleasure that has strong

reinforcing properties in its own right (17). Such

stimulation activates neural pathways that carry

natural rewarding stimuli. Animals with electrodes implanted in these areas in such a way that

electrical impulses produce a pleasurable sensation will repeatedly press a bar, or do any other

required task, to receive electrical stimulation.

The fact that animals will forego food and drink

to the point of death or will willingly experience

a painful stimulus to receive electrical stimulation

of the reward system attests to the powerful

reinforcing characteristics of the reward system.

Most drugs of

rectly, affect the

abuse, either directly or indibrain reward system. This is

evident by the fact that administration of most

drugs of abuse reduces the amount of electrical

stimulation needed to produce self-stimulation

responding (28).

The reward system is made up of various brain

structures. The central component is a neuronal

pathway that interconnects structures in the middle part of the brain (i.e., hypothalamus, ventral

tegmental area) to structures in the front part of

the brain (i.e., frontal cortex, limbic system)

(15,16). A key part of this drug reward pathway

appears to be the mesocorticolimbic pathway

(MCLP) (figure 2-l). MCLP is made up of the

axons of neuronal cell bodies in the ventral

tegmental area projecting to the nucleus accumbens, a nucleus in the limbic system. The limbic

system is a network of brain structures associated

with control of emotion and behavior, specifically

perception, motivation, gratification, and memory. MCLP also connects the ventral tegmental

area with parts of the frontal cortex (medial

prefrontal cortex). Ventral tegmental neurons

release the neurotransmitter doparnine to regulate

the activity of the cells in the nucleus accumbens

and the medial prefrontal cortex. Other parts of

the reward system include the nucleus accumbens

and its connections with other limbic structures

like the amygdala and hippocampus, as well as to

other regions in the front part of the brain (i.e.,

substantial innominata-ventral palladium). There

are also connections from the nucleus accumbens

down to the ventral tegmental area. Finally, other

neuronal pathways containing different neurotransmitters (i.e., serotonin, opioids, gamma amino

butyric acid (GABA), glutamate, peptides) regulate the activity of the mesocorticolimbic doparnine system and are also involved in mediating

the rewarding properties of drugs of abuse.

These structures and pathways are thought to

play a role in the reinforcing properties of many

drugs of abuse, although the precise mechanisms

involved in all drugs of abuse lack a thorough

description. The mesocorticolimbic dopamine
Chapter 2—Basic Concepts | 11

Figure 2-l—The Mesocorticolimbic Pathway

Frontal -—---

cortex

Nucleus —

accumbens

tegmental v

area

The mesocorticolimbic pathway from the ventral tegmental

area to the nudeus accumbens and the frontat cortex is a key

component of the brain reward system for drug reinforcement.

SOURCE: Off Ice of Tdnobgy Assessment, 1993.

pathway appears to be critical in the rewarding

properties of stimulant drugs such as cocaine and

amphetamines (15,16,29). Also, both the ventral

tegmental area and the nucleus accumbens appear

to be important for opiate reward (7,15,16), while

these same structures and their connections to

other limbic areas, like the amygdala, may play a

role in the rewarding properties of barbiturates

and alcohol (15,16,20). Further details about the

brain areas involved in the rewarding properties

of various drugs of abuse are provided in chapter 3.

NEUROADAPTIVE RESPONSES

Exposure to drugs causes changes in the brain.

These changes are alterations in neurochemical

mechanisms related to the pharmacological action of a given drug. Often the change represents

a compensatory adjustment in the brain to return

the balance of activity back to normal after initial

exposure to the drug. Most drugs of abuse involve

complex actions in the brain resulting in a variety

of behavioral effects. Often, the type of neuroadaptive response that occurs to a drug is

opposite to its acute effects. Thus, the positive

reinforcing properties of drugs are replaced by the

negative reinforcing properties of withdrawal.

This indicates that neuroadaptive responses can

have motivational consequences that contribute

and play a role in an individual’s subsequent

drug-taking behavior. The specific details of the

biological mechanisms that underlie these phenomena are not completely understood, but recent

advances in neuroscience research have begun to

unravel how neuroadaptive responses manifest

themselves for various drugs of abuse. As with the

immediate rewarding properties of these drugs,

some evidence suggests that there may be common underlying mechanisms to the neuroadaptive

responses related to reward mechanisms of various drugs of abuse (2). What follows is a general

description of neuroadaptive responses. Specific

details of possible biological mechanisms associated with the neuroadaptive responses of various

drugs are provided in chapter 3.

| Tolerance

Tolerance develops to a drug when, following

a prolonged period of use, more of the drug is

required to produce the same effect (10,14).

Tolerance occurs with many types of drugs. It is

a common, but unnecessary, characteristic of

drugs of abuse. There are two types of tolerance:

dispositional (pharmacokinetic) and pharmacodynamic.

DISPOSITIONAL

Dispositional tolerance develops when the

amount of drug reaching active sites in the brain

is reduced in some way. Generally, this arises

from an increased breakdown of the drug or a

change in its distribution in the rest of the body.

Thus, more drug must be taken to achieve the

same blood levels or concentrations at the active

sites in the brain.

PHARMACODYNAMIC

This form of tolerance represents a reduced

response of the brain to the same level of drug. It

develops during the continued and sustained

presence of the drug. It may be that the mechanism of adaptation may differ from drug to drug

and depend on the original mechanism of action
12 I Biological Components of Substance Abuse and Addiction

of a given drug. The net effect is that more drug

is required to overcome this new neuronal adaptation to produce an equivalent pharmacologic

effect.

Although dispositional tolerance represents a

component of tolerance to some drugs (e.g.,

alcohol, barbiturates), in most cases much or all

of the tolerance that develops to drugs with

significant abuse potential can be attributed to

pharmacodynamic tolerance (10,14). Tolerance

can contribute to drug-taking behavior by requiring that an individual take larger and larger doses

of a drug to achieve a desired effect.

I Dependence

Like pharmacodynamic tolerance, dependence

also refers to a type of neuroadaptation to drug

exposure. Dependence differs in that, with prolonged use of a drug, cells in the brain adapt to its

presence such that the drug is required to maintain

normal cell function. On abrupt withdrawal of the

drug, the neuron behaves abnormally and a

withdrawal syndrome ensues. Generally, the withdrawal syndrome is characterized by a series of

signs and symptoms that are opposite to those of

the acute effects of the drug. For example, on

withdrawal, sedative drugs produce excitation

and irritability. Conversely, stimulants produce

profound depression on withdrawal.

The magnitude of the withdrawal syndrome

varies from drug to drug. With some drugs very

mild withdrawal occurs, whereas with others

(e.g., alcohol, barbiturates) the withdrawal syndrome can be so severe that it is life-threatening.

No matter the severity of the withdrawal syndrome, its existence can create a craving or desire

for the drug and dependence can play a very

strong role in recurrent patterns of relapse, in

maintaining drug-seeking behavior to forestall

the withdrawal syndrome, and in the need to

reestablish some sense of normalcy.

| Residual Tolerance and Dependence

 In general, expression of tolerance and dependence has been considered to be rate-limited in that

tolerance to most drugs gradually dissipates with

time as the brain readapts to the disappearance of

the drug and withdrawal peaks within hours or

days after discontinued use and then dissipates.

However, substantial evidence indicates that

there may be persistent or residual neuroadaptation that lasts for months or years (10,27). For

example, craving and drug-seeking behavior have

been reported to last for years with nicotine,

alcohol, and cocaine suggesting some residual

effect of drug use that may or may not dissipate

with time. Moreover, there is a phenomenon that

characterizes drug-dependent individuals. Specifically, with repeated cycles of abstinence and

reinitiation of drug use, the time required to elicit

drug dependence grows shorter and shorter.

Furthermore, there is evidence that the administration of naloxone, a drug that blocks the actions

of opiates, may elicit a withdrawal syndrome in

individuals who have abstained from use for

extensive periods of time. These data indicate that

some residual neuroadaptive changes induced by

drugs persist for as yet undefined periods of time.

Little information is available about the mechanisms involved in this effect, but it is clear that

residual neuroadaptive changes may persist for

extended periods of time in former drug users and

that they may account for the striking relapses that

occur in long-term abstinent drug-dependent

individuals.

I Sensitization

Sensitization occurs when the effects of a given

dose of a drug increase after repeated administration. Thus, sensitization is the opposite of tolerance. Sensitization to a drug’s behavioral effects

can play a significant role in supporting drugtaking behavior.
Chapter 2–Basic Concepts | 13

ABUSE LIABILITY

The abuse liability of a drug is a measure of the

likelihood that its use will result in drug addiction. While many factors ultimately play a role in

an individual’s drug-taking behavior, the abuse

potential of a drug is related to its intrinsic

rewarding properties and the neuroadaptive responses that result from prolonged use. Drugs can

be tested and screened for their abuse liability.

The conceptual framework to screen drugs for

their abuse potential is virtually the same for all

drugs: opiates, stimulants, depressants, hallucinogens, and inhalants (l). The criteria that can be

evaluated to classify a drug as having significant

abuse potential are: pharmacological equivalence

to known drugs of abuse, demonstration of

reinforcing effects, tolerance, and physical dependence. The capacity to produce reinforcing

effects is essential to any drug with significant

abuse potential, whereas tolerance and physical

dependence most commonly occur but are not

absolutely required to make such a determination.

Testing new pharmaceuticals for their abuse

potential is an important step in new drug

development. The emphasis of many major pharmaceutical firms today is on the development of

new and safer drugs for pain reduction and in the

development of psychoactive compounds to treat

brain disorders. In particular, scientific strides in

understanding the brain, neurological disease,

psychiatric disturbances, and aging are fueling

research into treatment of brain disorders. As such

psychoactive compounds become available, they

must be screened for abuse potential. The abuse

liability assessment of new products is not simply

at the discretion of the manufacturer. As discussed in appendix A, various Federal regulatory

laws mandate such testing and Federal regulatory

agencies are charged with seeing that testing is

carried out.

Animal models are generally used to screen for

the abuse potential of new drugs in earlier stages

of drug development or to evaluate abuse potential in drugs that cannot be readily studied in

humans (l). Laboratory methods for abuse potential evaluation in humans are also well developed,

and this is an area of active research(8). However,

factors such as the heterogeneity of drug using

populations, the use of multiple drugs, and the

other biological, social, and environmental factors involved in human drug use make human

studies complex.

At first glance, it would seem impossible to

mimic in an animal the highly complex syndrome

of drug abuse in humans. However, paradoxically, the apparent limitations of animal models

are actually their strengths. Specifically, the

simplicity of an animal model obviates the

problems inherent in the complexity of humans:

the experimenter has strict control of environmental factors, drug use experience and patterns,

and individual differences that permit study of the

pharmacological and biological mechanisms associated with the development of addiction potential. Thus, the use of animal models permits

the highly complex syndrome of human drug

addiction to be dissected into separate components without the intrusion of a series of confounding variables found in humans.

In terms of the validity of animal models as a

means of studying human drug addiction, an

excellent correlation exists between predicting

the abuse liability of specific classes of drugs in

animals and humans (12). However, it must be

recognized that animal models are not perfect

and, in fact, there are examples of drugs that

proved to have significant abuse potential in

humans, whereas the preclinical testing in animals revealed relatively minimal abuse potential

(6,10,14). Thus, the ultimate answer to the issue

of whether a drug has significant abuse potential

is long-term experience with the drug once it has

become available, either legally or illegally.

Nevertheless, animal models serve as the only

practical means of initially screening drugs for

abuse liability and have proven to be the most

effective means of detecting whether there is

likely to be a problem in humans.
14 I Biological Components of Substance Abuse and Addiction

Self=Administration

The predominant feature of all drugs with

significant addiction-producing properties is that

they are self-administered (3,5,9,11). In fact,

self-administration of a drug to the point when the

behavior becomes obsessive and detrimental to

the individual is the primary criterion for classifying a drug as having significant potential for

addiction. In addition to self-administration, another predictor of drug addiction is the notion of

craving and the tendency to relapse or increase

use during withdrawal (6, 10,14). Although craving is a difficult term to quantify, once a drug is

voluntarily or involuntarily withdrawn, the desire

to take it can play a role in the relapse to substance

abuse. As previously mentioned, the reinforcing

properties of the drug underlying craving maybe

shifted from the pattern established during the

initial, early phase of drug addiction. Specifically,

the drug may have initially been self-administered for its pleasurable effects but may eventually be self-administered to relieve the discomfort

associated with withdrawal. Thus, the primary

motivation for using the drug can be that the

individual needs the drug to function normally.

Animals can be readily trained to selfadminister drugs (6). Which experimental technique is used depends on the class of compounds,

a drug’s normal route of administration in humans, and methodological concerns (e.g., solubility of the drug). While the reasons animals initiate

drug-seeking behavior are dictated by the experimental situation, rather than intrinsic dispositional factors as in humans, the pattern of use once

established fulfills all of the criteria of drug

addiction: compulsive drug-seeking behavior to

the point of detrimental effects on the animal and

enhanced attempts of self-administration during

withdrawal.

The technique of self-administration is a powerful tool and provides a good indication of the

abuse liability of new or unknown drugs (l). For

example, substitution studies can be used to

determine whether, and over what dosage ranges,

drugs have reinforcing effects. In addition, the

efficacy of drugs as reinforcers can be evaluated

using the amount of work animals will perform to

obtain drug injections or how they make selections between drug reinforcers. By making comparisons of the self-administration rates of unknown compounds with known standard reference drugs, it is often possible to estimate the

reinforcing property of the drug relative to the

standard. Thus, by using self-administration techniques, one can assess the relative reinforcing

strengths of a drug and also examine the behavioral, physiological, and biological factors that

lead to sustained self-administration.

I Drug Discrimination

Drug discrimination is another tool used in the

assessment of abuse liability of drugs in animals

(3,6). Drug discrimination refers to the perception

of the effects of drugs. Specifically, animals or

humans trained to discrimin ate a drug from

placebo show a remarkable ability to distinguish

between the effects of the drug from other drugs

possessing different properties. The procedures

also permit a determination of whether the animal

considers the drug to be the pharmacological

equivalent of another drug. Pharrnacologicalequivalence refers to the fact that drugs of a particular

class, such as opiates, stimulants, and depressants, produce a unique series of effects on the

brain and other organs that collectively constitute

their pharmacological profile. Thus, although

drugs may vary considerably in their chemical

structure, similar pharmacological effects indicate specifically how they actually interact with

and influence the behavior of the intact organism.

While animals cannot express whether a drug’s

subjective effects are similar or dissimilar to

another, various behavioral experiments can be

used to determine whether an animal perceives

drugs to be pharmacologically dissimilar or

equivalent. For example, animals can clearly

distinguish opiates from stimulants or other
Chapter 2–Basic Concepts I 15

depressants, but may be unable to distinguish one

opiate of the same type from another.

| Dependence and Tolerance

Dependence and tolerance can readily be

induced in animals by either volitional or passive

means (13,14). Specifically, using a selfadministration model, animals often will develop

tolerance and dependence characterized by increased amounts of drug self-administration and/

or enhanced rates of self-administration. Following abrupt withdrawal of the drug, a withdrawal

syndrome will often develop and, if given the

opportunity, self-administration rates will be

increased. Alternatively, it is often easier to

induce tolerance and physical dependence passively by injecting large amounts of drug into

animals for prolonged periods of time. In this

case, neuroadaptation occurs quickly and predictably. This technique has the advantage that the

experimenter can exercise complete control of

doses and times required to produce tolerance and

dependence. In either case, it is possible to induce

neuroadaptation in animals that can then be

experimentally manipulated. Furthermore, since

the understanding of the neuroadaptive changes

that take place during the development of tolerance and physical dependence are poorly understood in humans, animal models offer a unique

opportunity to carry out experiments designed to

address these issues.

I Interpretation of Results in Animals and

the Concept of Thresholds

Once a drug has been classified as having

significant abuse potential, two central questions

remain: first, does this information pertain to

humans; and, second, can one rate the relative

abuse potential of drugs in animals (e.g., Does

drug A have five times the abuse liability of drug

B?). with regard to the frost point, results from

animal testing generally have been excellent

predictors of abuse liability of drugs in humans,

but a small number of exceptions mandate that

final drug testing be carried out in humans.

Nevertheless, animal testing is an accepted predictor of abuse potential in humans and must be

carried out to provide the basis for additional

screening in humans.

In terms of rating the abuse liability of drugs in

animals, the degree of abuse liability that can be

expected from a drug of abuse can be determined

using the animal testing procedures outlined

above. For example, by comparing the degree to

which a drug satisfies the criteria outlined above,

such as the amount of work that will be performed

to self-administer the drug and the strength of the

physical dependence, general conclusions about

the abuse potential of an unknown drug by either

comparison to drugs of a similar class or different

classes of drugs can be made.

while tests show that a drug has abuse potential, the problem it poses in humans ultimately

depends on the overall effects of the drug and the

extent to which self-administration of the drug

represents a problem to the individual or society.

Relative abuse potential and its severity must be

considered in terms of the consequences not only

to the person, but also in the societal and

environmental context in which it occurs.

ROLE OF LEARNING

Another significant contributing force in drug

abuse is the learning that can occur during an

individual’s drug-taking activity (18,23).

In addition to producing pleasant feelings in

the user and having rewarding properties, drugs of

abuse produce changes in numerous organ systems such as the cardiovascular, digestive, and

endocrine systems. Both the behavioral and

physiological effects of a drug occur in the

context of an individual’s drug-seeking and

drug-using environment. As a result, there are

environmental cues present before and during an

individual’s drug use that are consistently associated with a drug’s behavioral and physiological

effects. With repetition the cues become conditioned stimuli, that on presentation, even in the
16 I Biological Components of Substance Abuse and Addiction

absence of the drug, evoke automatic changes in

organ systems and behavioral sensations that the

individual may experience as drug craving. This

is analogous to Pavlov’s classical conditioning

experiments in which dogs salivate on the cue of

a bell, following repeated pairing of food presentation with a ringing bell. Evidence for this effect

is seen in numerous studies showing that animals

seek out places associated with reinforcing drugs

and that the physiological effects of drugs can be

classically conditioned in both animals and humans (12). Thus, exposure to environmental cues

associated with drug use in the past can act as a

stimulus for voluntary drug-seeking behavior. If

the individual succeeds in finding and taking the

drug, the chain of behaviors is further reinforced

by the drug-induced rewarding feelings and the

effects of the drug on other organ systems (18).

Drug conditioning can help explain the fact that

many drug abusers often return to environments

associated with drug use, even after being counseled not to. The effects of the environmental

stimuli can be similar to the priming effects of a

dose of the drug.

Also, it has long been known that conditioning

occurs in relation to the withdrawal effects of

drugs (26). It was observed that opiate addicts

who were drug free for months and thus should

not have had any signs of opiate withdrawal,

developed withdrawal symptoms (e.g., yawning,

sniffling, tearing of the eyes) when talking about

drugs in group therapy sessions. This phenomenon, termed conditioned withdrawal, results from

environmental stimuli acquiring the ability,

through classical conditioning, to elicit signs and

symptoms of pharmacological withdrawal. Conditioned withdrawal can also play a role in relapse

to drug use in abstinent individuals. The emergence of withdrawal symptoms as a result of

exposure to conditioned cues can motivate an

individual to seek out and use drugs.

Studies have also demonstrated that, once

established, conditioned associations are difllcult

to reverse (23). In theory, repeated presentation of

the environmental cues, without the drug, should

extinguish the conditioned association. Animal

studies indicate that extinction is difficult to

achieve and does not erase the original learning.

As a result, once established, the extinction is

easily reversed. Animal studies examining drug

conditioning have found that various aspects of

extinguished responses can either be reinstated

with a single pairing of the drug and environmental cue, can be reinstated with a single dose of

drug in the absence of the environmental cue, or

can spontaneously recover (23).

The biological mechanisms underlying conditioned drug effects are just beginning to be

described. Recent evidence links the mesocorticolimbic system to these effects. Studies have

found increased release of dopamine in the

nucleus accumbens associated with anticipated

voluntary alcohol consumption (18,19,24,25).

Other studies have presented evidence that destruction of MCLP blocks the conditioned reinforcing effects of opiates (4,21,22). The excitatory amino acid neurotransmitters may also play

a role in drug conditioning effects. As the name

implies, excitatory amino acids are a class of

neurotransmitter that act to stimulate neuronal

activity in the brain. These amino acids have been

implicated in learning and memory. Injection of

a drug that blocks the activity of the excitatory

amino acids has been shown to block the develop

ment of conditioned amphetamine effects (23).

Finally, there is evidence that genetic factors may

play a role in the conditioning phenomena associated with drug use (see ch. 4).

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Chapter 2–Basic Concepts | 17

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The

Neuropharmacology

of Drugs

of Abuse 3

rugs of abuse interact with the neurochemical mechanisms of the brain. Some of these interactions are

directly related to the reinforcing properties of a drug,

while others are related to other effects associated with

the drug. As in other areas of neuroscience, the level of

understanding about these interactions and the mechanisms

involved has increased tremendously over the last decade. The

fundamentals of information processing in the brain and how

psychoactive drugs can alter these processes are being elucidated. For drugs of abuse, certain commonalities have begun to

emerge. While drugs of abuse have a wide range of specific

individual actions in the brain, there is growing evidence that

their reinforcing properties may result from a shared ability to

interact with the brain’s reward system. For each drug of abuse,

this action, coupled with its actions in other areas of the brain,

contributes to the overall behavioral effect the drug produces. In

some cases, the relationship of a drug’s neurochemical action and

the behavioral effects it produces have been clearly elucidated,

while in others much remains to be learned.

This chapter describes how drugs of abuse affect neurochemical activity and the mechanisms that may underlie the characteristics contributing to and determining a drug’s abuse potential,

namely, their reinforcing affects, the neuroadaptive responses

associated with them, and the development of withdrawal

symptoms. A brief summary of basic neuropharmacology is

provided to give general background information on how drugs

work in the brain.

, 0

I

19
20 | Biological Components of Substance Abuse and Addiction

NEUROPHARMACOLOGY

Neurons are the cells that process information

in the brain. Neurotransmitters are chemicals

released by neurons to communicate with other

neurons. When a neuron is activated it releases a

neurotransmitter into the synapse, the gap between two neurons (see figure 3-l). The molecules of the neurotransmitter move across the

synapse and attach, or bind, to proteins, called

receptors in the outer membrane of an adjacent

cell. Once a neurotransmitter activates a receptor,

it unbinds from the receptor and is removed from

the synapse. This is done either by the neurotransmitter being taken back up into the neuron that

released it (a process called reuptake) or by being

chemically broken down. Usually the axon terminal is the part of the neuron that releases

neurotransmitters into the synapse, and the dendrites and cell body are the areas of the neuron

that contain receptors that form synapses with the

axons of other neurons.

For each neurotransmitter in the brain, there are

specific receptors to which it can attach. Binding

by the neurotransmitter activates the receptor,

which can have different effects depending on the

receptor. Receptors can be linked to a variety of

membrane and cellular mechanisms that are

turned on or off by the activation of the receptor.

Some receptors open or close ion channels (i.e.,

for charged molecules such as potassium, sodium,

calcium, or chloride) in the membrane of the cell.

These channels regulate the flow of ions in and

out of the cell. The relative concentration of ions

between the inside and outside of a neuron is

crucial in the activity of the neuron. Other

receptors activate or inhibit intracellular mechanisms called second messengers. There are a

number of different second messengers that

control various aspects of cellular activity.

A neuron can have thousands of receptors for

several different neurotransmitters. Some neurotransmitters activate neurons (excitatory neurotransmitters), while others decrease neuronal

activity (inhibitory neurotransmitters). Sometimes

Figure 3-l—The Synapse and Associated

Structures

M( Nerve impulse

v

Neurotransmitters Receptors

Receiving cell

SOURCE: Office of Technology Assessment, 1993.

a receptor for one neurotransmitter can affect a

receptor for another neurotransmitter. In such

case, the receptors are biochemically coupled: the

activation of one modulates the function of the

other, either increasing or decreasing its activity.

A neuron can also have receptors for the neurotransmitter it releases; these are usually located

near the site where the neurotransmitter is released into the synapse. Such receptors are acted

on by the neuron’s own neurotransmitter to

regulate the release of the neurotransmitter. Thus,

these autoreceptors, as they are called, act as a

feedback mechanism to regulate a neuron’s activity. The activity of a neuron will be determined by

the cumulative activity of all of its various

receptors. Activation of a neuron generates an

electrical impulse inside the neuron that travels

from the cell body, down the axon, to the axon

terminal, where the impulse causes the release of

neurotransmitter into the synapse.

While receptors are specific for a neurotransrnitter, there may be a variety of receptor sub-
Chapter 3-The Neuropharmacology of Drugs of Abuse I 21

types, linked to different cellular mechanisms,

that all respond to the same neurotransmitter. In

this way one neurotransmitter can have diverse

effects in different areas of the brain. In addition,

neurons are connected to different circuits in the

brain, further accounting for diverse effects.

Many chemicals have been identified as neurotransmitters, among them dopamine, norepinephrine, serotonin, acetylcholine, various amino acids,

and peptides. As discussed in chapter 2, some of

these are of particular relevance to the rewarding

properties of drugs of abuse.

Psychoactive drugs alter these normal neurochemical processes. This can occur at any level of

activity including mimicking the action of a

neurotransmitter, altering the activity of a receptor, acting on the activation of second messengers, or directly affecting intracellular processes

that control normal neuron functioning.

In order to have these affects, a drug must enter

the brain, by diffusing from the circulatory system

into the brain. Routes of administration refers to

the methods used to deliver a drug into the

bloodstream. The route of administration affects

how quickly a drug reaches the brain. In addition,

the chemical structure of a drug plays an important role in the ability of a drug to cross from the

circulatory system into the brain. The four main

routes of administration for drugs of abuse are

oral, nasal, intravenous, and inhalation. With oral

ingestion, the drug must be absorbed by the

stomach or gut, which usually results in a delay

before effects become apparent, and must pass

through the liver where it can be chemically

broken down. Using the nasal route, effects are

usually felt within 1 to 3 minutes, as the capillary

rich mucous membranes of the nose rapidly

absorb substances into the bloodstream. Intravenous administration produces effects in 1/2 to 2

minutes and is slowed only by detour back

through the lungs that venous blood must take to

reach the brain. Lastly, the inhalation method

bypasses the venous system because the drug is

absorbed into the arterial blood flow, which goes

directly from the lungs to the heart and then to the

brain. As a result, effects are felt within 5 to 10

seconds, making inhalation the fastest route of

administration. The route of administration of a

drug can determine the potency and efficacy the

drug will have on affecting brain activity. In some

cases, the route of administration can also contribute to the abuse potential of a drug.

DRUGS OF ABUSE

I Stimulants

As the name implies, stimulant drugs have an

energizing effect that promotes an increase in

psychological and/or motor activity. Stimulants

such as cocaine and the amphetamines have their

most pronounced effect on the monoamine neurotransmitters (i.e., dopamine, serotonin, norepinephrine, and epenephrine) in the brain. They

also stimulate the physiological mechanisms that

are triggered in stressful situations (the ‘‘fight or

flight” response) via activation of the sympathetic nervous system. These include increases in

heart rate and blood pressure and the release of

various hormones. The arousing and euphoric

effects associated with these drugs are associated

with these various actions. Other stimulant drugs

are caffeine and nicotine. These drugs have

various mechanisms of action, but their net effect

is to stimulate central nervous system (CNS)

activity.

COCAINE

Cocaine is found in the leaves of the Erythroxylon coca plant, a large shrub indigenous to South

America. The compound is extracted from the

leaves and is then processed into either paste,

powder, or freebase form. The paste is the most

rudimentary, unrefined form. Additional processing of the paste by adding hydrochloric acid

produces cocaine powder (cocaine hydrochloride). Cocaine powder is often administered via

nasal insufflation (i.e., snorting). Freebase cocaine is the pure cocaine base released from

cocaine hydrochloride by further separation using

simple chemicals such as ether or sodium hydrox-
22 I Biological Components of Substance Abuse and Addiction

ide. This freebase cocaine is easily absorbed into

the membranes of the relatively alkaline environment of the body. The well-known “crack”

cocaine is simply baking soda and water mixed

with the base to create a solid form of freebase

cocaine which is immediately and completely

absorbed by the body when smoked. The most

common routes of administration for cocaine are

smoking and snorting although the intravenous

route is also used and is often preferred by those

who also inject other drugs, such as opiates (45).

In humans, cocaine produces an elevation in

mood and a sense of increased energy and

alertness. This can include an improvement in

concentration and attention, a reduction in the

sense of fatigue and performance decrement

caused by sleep deprivation, appetite suppression,

and an increase in libido. The toxic effects of high

doses of cocaine include delirium, seizures,

stupor, cardiac arrhythmias, and coma. Seizures

can result in sustained convulsions that stop

breathing.

Acute administration—The most prominent

pharmacological effect of cocaine is to block the

reuptake of dopamine back into the presynaptic

terminal once it has been released from a neuron

terminal (61), resulting in increased levels of

dopamine at its synapses in the brain (see figure

3-2). The specific uptake site for dopamine has

been identified and cocaine’s actions on the

mechanism that transports dopamine back into

the neuron is an active area of research. Within the

brain mesocorticolimbic pathway (MCLP), levels

of dopamine increase in the synapses between the

terminals of the neurons projecting from the

ventral tegmental area and the neurons in the

nucleus accumbens and medial prefrontal cortex

(60,62). In addition to blocking dopamine reuptake, cocaine also blocks the reuptake of norepinephrine and serotonin (62).

The acute behavioral effects of cocaine are the

result of these neurochemical actions. The acute

reinforcing properties of cocaine are due to its

capacity to enhance the activity of dopamine in

MCLP. As with most neurotransmitters, doparnine has a number of receptor subtypes distributed in different brain areas. The reinforcing

properties of cocaine are mediated via dopamine

activation of at least two of these, the DI and D2

dopamine receptor subtypes (39,62), and more

recently there is evidence for an action at D3 receptors (12). The increase in dopamine activity

via D2 and D1 receptors is also important in the

other behavioral effects of cocaine (62). The role

of cocaine’s actions on brain norepinephrine and

serotonin uptake in its behavioral effects has not

been clearly established (62).

Chronic administration-Chronic administration of cocaine activates a number of brain

neurochemical compensatory mechanisms, the

details of which are not completely understood.

Both short- and long-term changes in the dynamics of neurotransmission following repeated cocaine administration have been observed in experiments. Results from animal studies indicate

that continued administration results in a sustained increase in dopamine levels within the

synapses of the nucleus accumbens (60). This is

believed to be due to a decreased sensitivity of

dopamine autoreceptors, which regulate the release of dopamine from the presynaptic terminal.

In their normal state, these autoreceptors decrease

the amount of dopamine released into the synapse. Changes also seem to occur in the number

of postsynaptic receptors for dopamine, but the

exact nature of these changes has yet to be

characterized. Both increases and decreases in

receptor numbers have been reported (62). The

exact effects of chronic cocaine administration

seem to vary among receptor subtypes and

locations.

A number of changes in the intracellular

mechanisms, including second messenger systems, involved in the activity of dopamine

neurons in the ventral tegmental area and nucleus

accumbens have been described following chronic

cocaine administration (10). The changes are

thought to be due to alterations in the expression

of the genes that regulate and control the intracellular mechanisms. The net effect of these changes
— ..-

Chapter 3-The Neuropharmacology of Drugs of Abuse | 23

Figure 3-2-Cocaine’s Principal Action Mechanism

Dopamine terminal

\

Cooaine’s principal mechanism of action is to block the uptake

of dopamine into the presynaptic terminal. (Compare to figure

3-l.)

SOURCE: Office of Technology Assessment, 1993.

is to reduce the capacity of ventral tegmental

neurons to transmit dopamine signals to the

neurons in the nucleus accumbens. This could

represent a mechanism by which tolerance to the

rewarding properties of cocaine could develop

and could contribute to cocaine craving. Importantly, these changes are lacking in other dopamine pathways not involved in drug reward. Similar

changes were observed following chronic morphine administration . These findings suggest that

a common physiological response to chronic

administration of these drugs of abuse may exist.

Further investigations are necessary to completely characterize the changes that occur and to

determine whether they are typical for other drugs

of abuse.

Finally, animal studies have shown that repeated administration of cocaine causes changes

in the levels of other neurotransmitters, most

notably some of the peptide neurotransmitters.

These changes may result from alterations in

dopamine transmission that effect other areas of

the brain. These secondary responses indicate that

the neurochemical adaptive response to repetitive

cocaine administration involves a complex interaction between multiple neuronal pathways and

neurotransmitter systems (62).

Matching the pharmacological profile, the

behavioral response to repeated cocaine administration is also complex. Results from animal

studies suggest that how the drug is administered

can affect whether sensitization or tolerance

occurs. Intermittent administration of cocaine can

trigger sensitization to some of its specific motor

effects, such as stimulating levels of activity

(61,62). Conversely, tolerance to these motor

effects develops when the drug is given continuously (62). While it is unclear whether tolerance

develops to cocaine’s reinforcing effects, experimental evidence suggests that it does and subjective reports from cocaine users that the euphoric

actions of the drug diminish with repeated use

support the notion (45,62). Increasingly, experimental evidence suggests that chronic cocaine

administration increases drug craving (36,42).

A withdrawal reaction occurs with the abrupt

cessation of cocaine administration after repeated

use. This reaction is marked by prolonged sleep,

depression, lassitude, increased appetite, and

craving for the drug (61). In animal studies,

cocaine withdrawal results in an increase in the

level of electrical stimulation necessary to induce

a rat to self-stimulate the brain reward system

(40). This indicates that during cocaine withdrawal, the brain reward system is less sensitive.

While the precise pharmacological mechanism

underlying this withdrawal is unknown, it is

suspected that it relates to some hypoactivity in

dopamine functioning within the brain reward

system (40). Changes in the expression of genes

that control intracellular mechanisms (10) represent a possible mechanism that could account for

this change and could contribute to the drug

craving associated with chronic cocaine use.

Avoidance of the withdrawal reaction can be
24 | Biological Components of Substance Abuse and Addiction

another important determinant in continued cocaine use.

AMPHETAMINES

Amphetamines (i.e., dextroamphetamine, methamphetamine, phemetrazine) produce effects similar to cocaine (20). Amphetamine users describe

the euphoric effects of the drug in terms indistinguishable from those used by cocaine users and in

the laboratory, subjects cannot distinguish between the subjective effects of cocaine and

amphetamine (36). This is not to suggest that

cocaine and amphetamine have identical mechanisms of action or that under properly selected

experimental conditions differences between their

effects cannot be demonstrated. For example,

cocaine effects are relatively brief after intravenous injection, whereas those of methamphetamine may last for hours (36). Oral ingestion is the

most common route of administration of amphetamines, although intravenous injection, smoking,

and nasal insufflation are also used.

Acute administration—Like cocaine, acute

amphetamine administration results in mood

elevation and increased energy. In addition, the

user may experience feelings of markedly enhanced physical strength and mental capacity.

Amphetamines also stimulate the sympathetic

nervous system and produce the physiological

effects associated with sympathetic activation.

High doses of amphetamine produce a toxic

syndrome that is characterized by visual, auditory, and sometimes tactile hallucinations. There

are also feelings of paranoia and disruption of

normal thought processes. The toxic reaction to

amphetarnines is often indistinguishable from an

episode of the mental disorder schizophrenia.

Not surprisingly, action of amphetamines is

similar to cocaine. The reinforcing properties of

these drugs is due to their ability to enhance

dopamine action in MCLP. However, while

amphetamines also block dopamine reuptake,

their most significant action is to directly stimulate the release of dopamine from neurons (61)

(figure 3-3). Thus, unlike cocaine, which blocks

Figure 3-3-Amphetamines’ Principal

Action Mechanism

r ‘

-

7 7

-

”

-

”

-

Nerve Impulse

\

‘ \

Amphetamines

\ $ /“

P

b \,

■ ■ ■

I

Amphetamines’ principal mechanismism of action is to stimulate

the release of dopamine from the presynaptic terminal.

(Compare to figure 3-1.)

SOURCE: Office of Technology Assessment, 1993.

dopamine reuptake following normal release of

the transmitter from the terminal, the amphetamine increase in dopamine activity is independent of neuronal activity (61). As a result of this

difference, amphetamines are more potent than

cocaine in increasing the levels of dopamine in

the synapse. Amphetamines also directly stimulate the release of norepinephrine, epinephrine,

and serotonin from neurons. Among the amphetamines, the balance between their actions on these

different neurotransmitter systems vary. For

example, methylenedioxymethamphetamine

MDMA) has a particularly potent effect on the

serotonin system, which imbues this drug with a

psychedelic effect.

Chronic administration—As with cocaine,

both sensitization and tolerance to different effects of amphetamines occur. Animal studies

have shown that intermittent administration of
Chapter &The Neuropharmacology of Drugs of Abuse | 25

amphetamine es results in sensitization to the

motor stimulating effects (61). This sensitization

is thought to be due to an augmentation of

dopamine release after intermittent, repeated drug

administration. Tolerance to the euphoric effects

of amphetamine develops after prolonged, continuous use (45). Such tolerance is believed to be

caused by depletion of stored neurotransmitters,

especially dopamine, in the presynaptic terminals

as a result of the continued stimulation of release

from the stores by the drug. Drug craving is

increased with continued amphetamine use (36,42).

Finally, a withdrawal syndrome, similar to cocaine’s, is produced with the cessation of amphetamine administration after prolonged use.

CAFFEINE

Caffeine is the most widely used psychoactive

substance in the world (28,33). Surveys indicate

that 92 to 98 percent of adults in North America

regularly consume caffeine, mostly in coffee or

tea (28). Caffeine belongs to a class of compounds

called methylxanthines, which act as CNS stimulants (49). The stimulating effects of caffeine are

due to its ability to block the receptors for the

inhibitory neurotransmitter adenosine (49). Caffeine blocks both the Al and A2 adenosine

receptor subtypes, having its more potent effect

on the A 1 receptor (49). Adenosine inhibits the

release of various neurotransmitters, in particular

the excitatory amino acid glutamate. Therefore,

caffeine blockade of adenosine receptors results

in increased glutamate activity. Caffeine also

increases the levels of norepinephrine and serotonin, which contributes to the drug’s CNS

stimulating effects (49). Caffeine’s effects on

dopamine are unclear in that increases, decreases,

or no change in the release of dopamine have been

observed following caffeine administration in

various experiments (49).

In humans, caffeine has a general alerting

affect, and it has been shown to increase locomotor activity in laboratory animals (49). However,

experimental evidence indicates that in humans

there is great individual variability in caffeine’s

effects (49). These differences are linked to

differences in rates of caffeine absorption from

the gastrointestinal system and metabolism in the

body. Age also seems to affect the response to

caffeine, in that older people show an increased

sensitivity to caffeine’s stimulating effects (49).

This is particularly true of caffeine’s disruptive

effects on sleep.

Acute administration-caffeine exhibits, at

most, weak reinforcing effects in animal selfadministration experiments (28,33). The level of

responding induced by caffeine is much less than

that seen with other stimulants such as amphetamine and cocaine (33). In humans, experiments

demonstrate that caffeine’s reinforcing actions

are also minimal and dose-dependent (28,33).

Low doses are mildly reinforcing with subjects

reporting positive subjective effects, while higher

doses produce adverse effects. The results from

human studies indicate that reinforcement occurs

only under certain conditions and not across all

individuals (28). The mechanism of caffeine’s

reinforcing actions is unknown.

Chronic administration—Humans can develop tolerance to many of the physical manifestations of caffeine’s actions such as increased

heart rate and higher blood pressure and there is

evidence that tolerance develops to its behavioral

consequences including alertness and wakefulness (28,33,49). In animals, tolerance develops to

some of caffeine’s behavioral effects such as the

stimulation of locomotor activity (49).

A withdrawal syndrome has clearly and repeatedly been demonstrated after the cessation of

chronic caffeine consumption (28,33,49). Changes

in mood and behavior can occur with lethargy and

headache being the two most common symptoms

of caffeine withdrawal (28). These changes may

be the result of a compensatory increase in

adenosine receptors resulting from the chronic

blockade by caffeine. However, more studies are

needed to confirm this possibility (49).
26 | Biological Components of Substance Abuse and Addiction

NICOTINE

It is generally accepted that while people

smoke tobacco for many reasons (e.g., social,

cultural), the majority of people who smoke

tobacco do so in order to experience the psychoactive properties of the nicotine contained in

the smoke (4,56). Furthermore, a significant

proportion of habitual smokers become dependent on nicotine and tobacco smoking has all the

attributes of drug use considered to be addicting

(4,38). Nicotine activates one of the receptor

subtypes for the neurotransmitter acetylcholine

(38,56). As a result, this receptor is called the

nicotine receptor. The psychological effects of

nicotine are fairly subtle and include mood

changes, stress reduction, and some performance

enhancement (7).

When tobacco is smoked, nicotine is readily

absorbed by the lungs. Studies of smoking

patterns have shown that habitual smokers tend to

smoke more efficiently, because they inhale

longer, have shorter intervals between puffs, and

take a greater number of puffs per cigarette thus

increasing the dose of nicotine they receive (38).

Smokeless tobacco involves either chewing tobacco leaves or placing tobacco between the

cheek and gums. The blood nicotine level achieved

using smokeless tobacco can be comparable to

that achieved by smoking cigarettes. Because of

the route of administration, however, blood nicotine levels remain higher longer (45). Evidence

indicates that the diseases related to the use of

tobacco may be caused by different constituents

of tobacco or tobacco smoke. For example,

cardiovascular effects are related to carbon monoxide in the smoke, and the effects on the heart

and various cancers are probably due to carcinogens in the tobacco (36).

Acute administration—Nicotine stimulates

the release of dopamine from dopamine neurons

in the MCLP (4,56). This results from activation

of nicotine receptors that stimulate activity in

dopamine neurons in the ventral tegmental area.

However, when compared to the effects of

cocaine or amphetamine, the nicotine increase in

dopamine release is modest, and as a result,

nicotine is a comparatively weak reinforcer in

animal experiments (4,56). Nonetheless, nicotine

reinforcing properties are thought to be the result

of this action. “ Animal study results indicate that

activation of nicotine receptors also stimulates

the release of noradrenaline from neurons in the

locus ceruleus and may reduce serotonin activity

in the hippocampus (4). However, the exact

nature of these changes and the role they may play

in the behavioral effects of nicotine is unclear.

Chronic administration—Tolerance develops to many of the effects of nicotine and a

withdrawal syndrome marked by irritability, anxiety, restlessness, and difficulty in concentrating

develops when tobacco use stops (4,36,45). In

addition, a craving for tobacco, which may

subside in a few days, occurs (36). The pharmacological mechanisms underlying these changes

are unknown. Although animal studies have

suggested that chronic administration of nicotine

increases the number of nicotine receptors, the

mechanism that mediates this increase and the

possible involvement it plays in the tolerance and

withdrawal associated with nicotine remains to be

clarified (4,56).

| Phencyclidine

Phencyclidine (PCP) is representative of a

unique class of abused drugs that includes the

anesthetic ketamine and other drugs similar to

PCP. PCP was developed as an injectable anesthetic in the 1950s. However, PCP anesthesia is

quite dissimilar to that produced by typical

general anesthetics (6,8). It produces a dissociative state in which patients are generally unresponsive and perceive no pain. Patients are

amnesic for the surgery and CNS depression seen

with other general anesthetics is absent. Delirium

that often occurs on emergence from PCP anesthesia curtailed PCP’s use as an anesthetic in

humans. It is still sometimes used as a veterinary

anesthetic but is no longer marketed in the United

States.
Chapter 3-The Neuropharmacology of Drugs of Abuse | 27

At nonaesthetic doses PCP produces behavioral effects in common with several other drugs

including amphetamines, barbiturates, opiates,

and psychedelics (13). Given its wide range of

behavioral effects, PCP’S broad neurochemical

action in the brain is not surprising. PCP antagonizes the actions of the excitatory amino acid

neurotransmitter glutamate at the N-methyl-Daspartate (NMDA) receptor, one of the receptor

subtypes for glutamate (8,37). Glutamate is found

throughout the brain and increases the flow of

calcium ions into cells to cause excitatory actions.

The NMDA receptor controls the calcium ion

channel acted on by glutamate and binding of

PCP to the receptor blocks calcium entry into the

cell. It is likely that the diverse behavioral effects

of PCP are due to the fact that glutamate is widely

distributed in the brain and regulates the activity

of a number of other neurotransmitter systems.

PCP also affects brain dopamine systems in ways

similar to amphetamine (37).

The subjective effects of PCP administration

can vary dramatically depending on a user’s

personality and a user may experience vastly

different reactions during different drug-taking

episodes (13). In most cases, low doses produce

euphoria, feelings of unreality, distortions of

time, space, and body image, and cognitive

impairment. Higher doses produce restlessness,

panic, disorientation, paranoia, and fear of death.

As with its use as an anesthetic, PCP often causes

amnesia to occur beginning immediately after the

drug is taken until its effects begin to wear off.

PCP is often associated with violent behavior in

users but laboratory studies indicate that it does

not increase aggressive behavior in animals (6). In

fact, the bulk of evidence indicates that PCP

decreases aggression at most doses under most

experimental conditions (6). The violence often

associated with PCP use is likely to be due to a

combination of its multiple effects including its

ability to block pain and its stimulant and

psychedelic actions.

Acute administration—In animal studies, PCP

has been shown to be a highly effective reinforcer

(6,13). From clinical reports of human PCP use

and from animal studies, route of administration

appears to affect the self-administration rate.

Intravenously delivered PCP has been established

as a reinforcer in rats, dogs, and primates. Oral

PCP is rapidly established as a reinforcer in

primates but not in rats (13). In humans, the most

common route of administration of PCP is

smoking.

The mechanism of action of PCP’S reinforcing

effects are unclear. Part of PCP’S behavioral

effects are similar to dopamine-stimulating drugs

like amphetamine (37) and its administration

potentates the sedating properties of alcohol and

barbiturates (6,13). As previously mentioned,

PCP blocks the action of glutamate at the NMDA

receptor. All of these actions may be relevant to

the production of its reinforcing effects.

Chronic administration—Repeated PCP administration has been shown to produce tolerance

to many of its effects in animals (6,13). The

magnitude of the tolerance, however, is less than

what is seen with most other drugs of abuse (13).

Systematic studies of PCP tolerance in humans

have been few, but chronic PCP users report that

after regular use they increase the amount of PCP

smoked by at least twice (13). Some evidence

from animal studies also suggests that sensitization may develop to PCP under certain conditions

(13).

A withdrawal syndrome occurs in animals that

have been chronically administered PCP (13). It

is characterized by signs of CNS hyperexcitability such as twitches, tremors, and increased

susceptibility to seizures. Although PCP withdrawal syndrome can be reliably produced in

animals, a withdrawal syndrome in humans has

yet to be clearly identified (13). Symptoms of

depression, drug craving, increased appetite, and

increased need for sleep have been reported to

occur between 1 week and 1 month after termination of chronic PCP use (57). The lack of clear

evidence of a PCP withdrawal syndrome in

humans may be due to the fact that the drug is

usually not taken in large enough quantities
28 I Biological Components of Substance Abuse and Addiction

and/or not frequently enough to produce symptoms (13).

The neurochemical mechanisms underlying

PCP tolerance and withdrawal are unknown.

Both, direct PCP-induced alterations in NMDA

receptors and secondary changes in other neurotransmitter systems as a result of altered glutamate activity could play a role.

| Sedatives

Alcohol, barbiturates, and benzodiazepines are

drugs that inhibit CNS activity. Many of the abuse

inhalants appear to produce similar effects to

these sedative/depressant drugs. Although all

these drugs have different specific mechanisms

of action in the brain, they all share the ability

to enhance the activity of the inhibitory amino

acid neurotransmitter gamma amino butyric acid

(GABA). In some cases activation of inhibitory

pathways in the brain, in turn, hampers other

inhibitory pathways. The effect of inhibiting an

inhibitory pathway is often the net activation of a

brain region. This mechanism of interfering with

other inhibitory pathways is thought to play a role

in the abuse potential of these drugs.

ALCOHOL

Alcohol differs from most other drugs of abuse

in that it has no known receptor system in the

brain (52). Alcohol affects a number of different

neurotransmitter systems through its action on the

membranes of neurons and the ion channels,

particularly those for calcium and chloride, that

lie within them (43). In general, alcohol inhibits

receptors for excitatory neurotransmitters and

augments activity at receptors for inhibitory

neurotransrnitters (52). For example, alcohol

enhances the activity of GABA by affecting ion

channels that are related to a subpopulation of the

GABAA receptor subtype (figure 3-4) and decreases the action of the excitatory amino acid

neurotransmitter glutamate, through inhibition of

the NMDA receptor (43,52,55). The net effect of

alcohol is to depress activity in the brain producing its characteristic sedating and intoxicating

effects. A similar spectrum of effects is seen with

barbiturates and benzodiazepines.

Acute administration—In humans, acute consumption of alcohol produces a sense of well

being and mild euphoria and studies have shown

that animals will orally self-administer alcohol.

Several lines of evidence have implicated dopamine, serotonin, GABA, and opioid peptides in

alcohol reinforcement.

Results from several types of studies indicate

that dopamine is involved in the acute reinforcing

effects of alcohol. Drugs that block the activity of

dopamine reduce alcohol self-administraticm in

rats (40,53). Also, depending on the dose, alcohol

may stimulate locomotor activity and produce an

increase in dopamine levels in the nucleus accumbens (60). Finally, data from genetic models of

alcohol preference, in which a strain of rats is bred

to have a higher than normal preference for

self-administering alcohol, indicate that alcoholinduced release of dopamine is higher in the

alcohol-preferring rats than in nonpreferring rats

(60). These data suggest that activation of the

MCLP is involved in the reinforcing actions of

alcohol. However, the precise mechanisms of this

activation are unclear.

Alcohol also is thought to enhance GABA

activity in specific parts of the brain. GABA

enhancement has been linked to the reinforcing

effects of alcohol by the observation that drugs

that block GABA activity also decrease alcohol

intake in alcohol-preferring rats, while drugs that

increase GABA activity act as a surrogate for

alcohol, maintaining alcohol preference during

alcohol withdrawal (27). In addition, an increase

in the number of GABA containing fibers has

been observed in the nucleus accumbens of

alcohol-preferring rats as compared with nonpreferring rats (34). Part of alcohol’s reinforcing

effects possibly are due to an increase of GABA

inhibition on other inhibitory neurons that decrease the activity of the dopamine neurons in the

ventral tegmental area. This chain of action would

have the ultimate effect of increasing the activity

of the dopamine neurons (27). However, the
Chapter &The

Figure 3-4-The GABAA Receptor Complex

Cell membrane

Inside the cell ‘-’4

The GABAA receptor complex is made up of a chloride ion

channel surrounded by a GABA receptor (GABA) and a

benzodiazepine receptor (BDZ). Activation of the GABAA

receptor complex increases the flow of chloride into a cell,

thereby inhibiting the activity of the cell.

SOURCE: Office of Technology Assessment, 1993.

experimental evidence supporting this idea is

equivocal (27). While it is clear that both GABA

and dopamine are involved in the reinforcing

affects of alcohol, the relationship between these

systems in this action is yet to be defined (27).

Some experimental evidence implicates serotonin in the reinforcing effects of alcohol, although that involvement is not as clear as for

dopamine and GABA. Alcohol-preferring rats

show a relative deficit in brain serotonin levels as

compared to nonpreferring rats (48) and evidence

suggests that alcoholic patients have lower levels

of serotonin than nonalcoholics (5). In animal

studies, drugs or experimental manipulations that

increase the levels of serotonin in the brain reduce

voluntary intake of alcohol (40). These results

would seem to indicate that part of the reinforcing

effects of alcohol is due to its inhibitory effect on

the serotonin system. However, a variety of

studies using animals with experimentally depleted serotonin levels has found that this manipNeuropharmacology of Drugs of Abuse | 29

ulation decreased alcohol consumption (40). Thus,

while serotonin seems to be involved in alcohol’s

acute reinforcing effects the exact mechanisms

that may be involved still need to be clarified. The

discrepancies observed in experiments may ultimately be explained by differential effects of

alcohol on serotonin receptor subtypes in various

brain regions.

In animal studies alcohol self-administration is

decreased by drugs that block the action of the

opioid peptide neurotransmitters and is enhanced

by drugs that mimic their action, suggesting a role

for these neurotransmitters in alcohol reinforcement (40). However, drugs that block opioid

peptide activity also suppress food and water

intake indicating that their action is not specific

for alcohol but is related to an inhibition of

consummatory behavior in general (40). Nevertheless, as a result of this experimental work

naltrexone, an opioid peptide blocking drug, has

been tested in alcohol dependent humans, where

it has been demonstrated to be a promising

adjunct to behavioral relapse prevention treatment (50,59).

Chronic administration—Repeated administration of alcohol results in tolerance to many of

its effects. Tolerance to the motor, sedative,

antianxiety, and anesthetic effects of alcohol has

been shown in animal studies and tolerance in

humans is indicated by the fact that dependent

individuals increase their consumption over time.

How alcohol tolerance develops is not clearly

understood, but since alcohol affects the activity

in a wide range of neurotransrnitter systems, it

may involve mechanisms common to many or all

of them. In particular, an adaptation in membrane

channels for the calcium ion following chronic

exposure to alcohol may play a significant role in

alcohol tolerance (43). Dispositional tolerance

also plays a role.

Alcohol withdrawal in animals is characterized

by CNS hyperexcitability. In humans this hyperexcitability results in anxiety, anorexia, insomnia,

tremor, disorientation, and sometimes hallucinations. In severe withdrawal a syndrome called
30 I Biological Components of Substance Abuse and Addiction

delirium tremens, marked by vivid hallucinations,

disorientation with respect to time and place, and

outbursts of irrational behavior, may develop.

In humans, the craving for alcohol during

periods of abstinence has often been considered a

prime factor underlying excessive alcohol use.

However, there is no evidence of a correlation

between development of physical dependence

and a specific craving for alcohol in experimental

.

animals (52). This same result has been noted in

human alcoholics in an experimental laboratory

situation (44). While avoidance of withdrawal

symptoms plays a role in continued alcohol use in

humans, the relationship between the development of the withdrawal syndrome and alcohol

craving during abstinence needs to be clarified

(52).

The CNS hyperexcitability associated with

alcohol withdrawal is thought to be related to

alcohol-induced alterations in the sensitivity of

GABA and glutamate receptors (40,43). Experimental evidence indicates that prolonged alcohol

exposure decreases the sensitivity of GABA

receptors (47) and increases the sensitivity of

glutamate receptors (24). With the cessation of

alcohol intake, these changes are manifested

throughout the brain as a decrease in the overall

activity of the inhibitory neurotransmitter GABA

and an increase in the activity of the excitatory

amino acid neurotransmitter glutamate.

BARBITURATES

Barbiturates are a class of drugs that depress

CNS activity. First introduced in the early 1900s,

barbiturates were widely prescribed as antianxiety agents and sleep aids, and to treat other

psychiatric conditions. However, their lethal overdose potential and high abuse potential, coupled

with the advent of the safer benzodiazepine

compounds curtailed their use starting in the

1960s (46).

Barbiturates’ sedative effects result from their

ability to increase GABA activity (54). Their

mechanism of action is through an augmentation

of the activity of one of the receptor subtypes for

GABA, the GABAA

receptor (see figure 3-4). The

GABAA receptor is linked to a chloride ion

channel. Stimulation of the receptor by GABA

opens the channel and increases the flow of

chloride into the neuron, which acts to inhibit the

cell’s activity. Barbiturates increase the amount

of time the chloride channel stays open thus

increasing the inhibitory effects of GABA.

Acute administration—The reinforcing properties of barbiturates have been clearly demonstrated in both animal and human studies (46).

. Animals readily self-administer barbiturates in a

variety of different experimental paradigms. In

humans, studies using self-report measures have

demonstrated that drug-experienced subjects, blind

to the identity of the drug, consistently give

barbiturates high rankings when asked to rate a

series of drugs as to ‘liking” or ‘would you take

this drug again?” Also, in controlled studies,

human subjects will work to receive barbiturates

and will do more work to receive the drug if the

available dosage is increased (46). The mechanism of barbiturate reward is unclear. Since one

of its major effects is to enhance GABA activity,

barbiturates, like alcohol, may increase GABA

inhibition of other inhibitory neurons that decrease the activity of the dopamine neurons in the

ventral tegmental area. Further studies are necessary to confirm this possibility.

Chronic administration—With continued use

some tolerance develops to most effects of the

barbiturates (46). Little tolerance develops to the

lethal dose. Unlike most other drugs of abuse,

both dispositional and phaxmacodynamic tolerance are important in the development of barbiturate tolerance. Barbiturate withdrawal is marked

by a severe and sometimes life-threatening withdrawal syndrome (46). Both anxiety and depression are common features, and with heavy,

prolonged use, the development of severe grand

mal tonic epileptic seizures can occur. The

neurochemical changes responsible for the pharmacodynamic tolerance and withdrawal syndrome have yet to be clearly established. Some

experimental evidence suggests that tolerance is
Chapter &The Neuropharmacology of Drugs of Abuse | 31

the result of the GABAA receptors becoming less

sensitive to the effects of barbiturates (54). With

drug cessation, the barbiturate stimulation of

GABA activity ceases and the action of the

desensitized receptors manifests itself as an

overall decrease in GABA activity, resulting in

withdrawal symptoms. Again, the hyperexcitability that results is similar to what occurs in alcohol

withdrawal.

BENZODIAZEPINES

Benzodiazepines are a class of drugs introduced in the 1960s as antianxiety agents (25).

They rapidly replaced barbiturates, which have

significant abuse potential, to treat anxiety and

other psychiatric conditions, Like barbiturates,

benzodiazepines have a general inhibitory effect

in the brain by enhancing GABA activity. But

unlike barbiturates’ nonspecific effect on chloride

ion channels, benzodiazepines act by binding to

a specific benzodiazepine receptor (21,54). The

presence of a benzodiazepine receptor in the brain

indicates the presence of a naturally occurring

endogenous neurotransmitter that normally interacts with the receptor. An endogenous benzodiazepinelike neurotransmitter has yet to be identified.

The benzodiazepine receptor is coupled with

the GABAA receptor (figure 3-4). Stimulation of

the benzodiazepine receptor increases the frequency of chloride ion channel opening in response to GABA binding to the GABAA receptor

(21). Also, benzodiazepines enhance the binding

of GABA to its receptor and the presence of

GABA enhances benzodiazepine binding. The

net affect of benzodiazepines is to augment

GABA activity at the GABAA receptor and

enhance GABA action, The antianxiety and other

sedative effects of the benzodiazepines are due to

this action.

Acute administration—Most benzodiazepines support only modest levels of selfadministration, much below the levels observed

with barbiturates, when given intravenously in

animal studies (25,46). When given orally, benzodiazepines do not induce self-administration in

animal studies (46). In humans, self-report studies, similar to those used to examine barbiturates,

have demonstrated that benzodiazepines yield

modest rankings of liking and that given a choice,

subjects consistently prefer barbiturates over

benzodiazepines (25,46), Since benzodiazepines

act selectively on GABA activity it is probable

that their mild reinforcing properties are due to

activation of GABA mechanisms similar to those

described for alcohol.

Chronic administration—Prolonged exposure to benzodiazepines results in tolerance to

their therapeutic and other effects (19,21). This

tolerance maybe due to a reduction in the

functional activity of GABA as a result of a

desensitization of the benzodiazepine receptor

caused by prolonged exposure to the drug (2 1). As

with alcohol and barbiturates, a withdrawal syndrome occurs following benzodiazepine drug

cessation due to a decrease in GABA activity. In

general, the characteristics of benzodiazepine

withdrawal are similar to barbiturate withdrawal,

but at typical benzodiazepine therapeutic doses

the magnitude of the symptoms are less severe

than seen in barbiturate withdrawal. Nonetheless,

since benzodiazepines are widely prescribed,

their ability to induce physical dependence at

therapeutic doses indicates that care must be

given in their administration (25).

| Opiates

The poppy plant, Papaver somniferum, is the

source of naturally occurring opium. This natural

substance contains more than 20 alkaloid compounds, including the drugs commonly known as

morphine and codeine. Illicit drugs such as heroin

and other semisynthetic opiates are derived by

altering morphine (20). Opiates are drugs, natural

or synthetic, which have opium- or morphine-like

activity. These drugs, when administered into the

body, mimic the body’s endogenous, or selfproduced, opioid peptide neurotransmitters (endorphins, enkephalins, and dynorphins). The

opioid peptide neurotransmitters are involved in
32 | Biological Components of Substance Abuse and Addiction

three major functions: modulation of pain perception and response to painful stimuli; reward; and

regulation of homeostatic functions such as food,

water, and temperature regulation (39). The

main types of opioid receptors have been identified in the brain— mu, delta, and kappa (18), all

of which are linked to second messengers in the

cell (14). In general, the opioid peptide neurotransmitters have an inhibitory effect on the

activation of neurons (18). Since morphine is

selective for the mu receptor, it is thought that the

activation of this receptor is responsible for the

reinforcing characteristics of opiates (18,39,40,41).

The overall acute and chronic effects of opiate

drugs in the brain involve many interactive brain

systems (39). Related to the function of endogenous opioid neurotransmitters, opiate drugs

produce a profound sense of euphoria and wellbeing coupled with sedation, relaxation, and

increase in pain threshold in humans.

Acute administration-Opiates have an immediate reinforcing effect and are readily selfadministered by humans and animals in experimental situations (40). The weight of experimental evidence favors a role for dopamine in the

rewarding effects of opiates, while other systems

may also be involved (18). Animal studies have

shown that opiates increase the activity of dopamine neurons in the ventral tegmental area (18,39,

40,41). This increase is via an indirect mechanism

(18). Within the ventral tegmental area neurons

contain the inhibitory neurotransrnitter GABA.

Those GABA containing neurons have mu receptors on them and form synapses with the dopamine neurons. Since opioids also inhibit neural

activity, when the mu receptors are activated by

opiates, the GABA receptors release less GABA,

which decreases the inhibition on the dopamine

cells, causing the dopamine neurons to become

more active. The net effect of this disinhibition is

to increase activity in the ventral tegmental

neurons, which release doparnine in the nucleus

accumbens. This increase in dopamine activity

results in the rewarding and motor stimulating

properties of opiate drugs. In addition to the

dopamine-dependent mechanism of opiate reinforcement, there appears to be another component

not involving dopamine (40,41). This second

component is thought to involve opiate activity

on the neurons of the nucleus accumbens and their

connections to other areas in the front of the ‘brain

(41).

Chronic administration—In general, repeated

administration of opiates results in the development of marked tolerance to their effects including their reinforcing effects (15,18). While the

precise mechanism of opiate tolerance is unclear,

one hypothesis is that chronic exposure causes a

desensitivity of opioid receptors (15,58). Repeated activation of the receptors by the drug

causes an uncoupling of the receptor from the

internal cellular mechanisms that are activated

when the receptors are stimulated normally (58).

Experimental evidence also suggests that chronic

exposure to opiate drugs may decrease the levels

of endogenous opioid neurotransmitters, contributing to the development of tolerance (58). The

decrease is believed to be due to an over

activation by the opiate drugs of mechanisms that

normally regulate the levels of neurotransmitter

(58).

Craving and withdrawal are two prominent

characteristics of chronic opiate administration.

In humans withdrawal is characterized by depression, irritability, insomnia, nausea, and weakness

(18,36). Chronic morphine administration, like

chronic cocaine administration, has been shown

to produce changes in the expression of genes

involved in a number of intracellular mechanisms

within neurons in the ventral tegmental area and

nucleus accumbens (10). These changes may

contribute to the craving and feelings of dysphoria

associated with withdrawal.

The locus ceruleus, a nucleus in the brainstem,

has been implicated in the physical signs of opiate

withdrawal (15,39,40). The locus ceruleus is

composed mainly of neurons containing noradrenaline. These neurons send fibers to numerous

brain structures including the cortex, hippocampus, and other structures in the front of the brain
Chapter 3-The Neuropharmacology of Drugs of Abuse | 33

and receive fibers from various structures, including a strong excitatory input from other areas in

the brainstem, The activity of locus ceruleus

neurons is inhibited by opioid neurotransrnitters

via activation of mu receptors (15). Animal

studies have shown that direct electrical stimulation of these neurons produces symptoms similar

to those seen in opiate withdrawal (15). Locus

ceruleus neurons become tolerant to the effects of

opiates after chronic exposure (15,39). An increased stimulation of the neurons in the locus

ceruleus via their brainstem excitatory inputs is

thought to occur during opiate withdrawal, resulting in the enhanced noradrenaline release at the

many brain sites that receive inputs from the locus

ceruleus (15).

| Cannabis

The different types of drugs made from Cannabis sativa are distinguished by the plant parts used

in preparing the drug. Marijuana consists mainly

of dried plant material such as cut leaves, stems,

seeds, and the flowering tops of the plants.

Hashish is the dried resin made from the flower

tops and sinsemilla is a variety of marijuana

selected for its particularly potent effects and

harvested before seed formation. Cannabis is

most frequently smoked, resulting in the rapid

delivery of the drug into the bloodstream, such

that effects may be felt within minutes and last for

2 t0 3 hours. Cannabis may also be administered

orally. However, the plasma concentration is

lower and takes about an hour to peak.

Cannabis sativa contains psychoactive cannabinoids. The primary psychoactive component

of Cannabis sativa is the cannabinoid delta-9-

tetrahydrocannabinol (THC). Most of the other

cannabinoids are either inactive or weakly active.

In addition, smoking marijuana produces hundreds of other compounds (2). While most

research has concentrated on evaluating the

molecular and biochemical mechanisms of THC

that underlie the actions of the cannabinoids,

these other compounds can also play a role in the

acute and long-term consequences of marijuana

use (2).

It has only been in the last few years that a

specific receptor for THC has been identified in

the brain (16,30). This receptor is linked to a

second messenger (14) and is localized to specific

brain regions including the hippocampus, cerebral cortex, cerebellum, and the axon terminals of

fibers that arise in the basal ganglia (a brain

structure in the front of the brain involved with

movement) and terminate in the globus pallidus (a

structure in the front of the brain involved in

movement and closely connected with the basal

ganglia) and substantial nigra (located in the

midbrain, next to the ventral tegmental area, it

contains dopamine neurons that send fibers to the

basal ganglia) (29,30). The characteristic cognitive (e.g., memory impairment) and motor (e.g.,

decreased motor coordination) effects of THC are

thought to be the result of its action on these

receptors (29). As with benzodiazepines, the

identification of a specific receptor for THC

suggests that there may be a naturally occurring

endogenous neurotransmitter in the brain that

normally interacts with the receptor. While not

positively identified, several candidates have

been proposed, including the chemical anandamide (16).

Since smoking marijuana results in the inhalation of many potentially psychoactive compounds in addition to THC, the subjective effects

of marijuana vary somewhat among individuals

(2). The behavioral response to marijuana may

vary as a function of dose, setting, experience, and

expectation of the user, the cannabinoid content

of the sample, and the compounds that are

produced as the marijuana is burned. Nevertheless, several behavioral effects are generally

ascribed to marijuana use (32). The most prominent feature is an initial period of euphoria. The

euphoria is often followed by a period of drowsiness and sedation. Perception of time is altered

and there is a dissociation of ideas, and distortions

in hearing and vision. Some studies have documented impairment on a variety of cognitive and
34 I Biological Components of Substance Abuse and Addiction

performance tasks involving memory, perception, reaction time, learning, and motor coordination (2). An amotivational syndrome, characterized by apathy, dullness and impairment of

judgment, concentration and memory, along with

loss of interest in pursuit of conventional goals,

has been described in the literature, and evidence

shows that this syndrome is a result of chronic

intoxication (35).

Acute administration-While marijuana produces a feeling of euphoria in humans, in general,

animals will not self-administer THC in controlled studies (29). Also, cannabinoids generally

do not lower the threshold of the amount of

electrical stimulation needed to get animals to

self-stimulate the brain reward system, as do other

drugs of abuse; although one series of studies has

shown that in the inbred lewis rat, THC not only

lowers the threshold for electrical self-stimulation

but also enhances the release of dopamine in the

nucleus accumbens (22). The enhancement of

dopamine release was blocked by drugs that block

endogenous opioid activity (22) indicating that

endogenous opioids can regulate this response.

The fact that these results have been observed in

an inbred strain of rat indicates that they have

some inherited variation related to the mechanism

of THC. Since THC receptors are not directly

associated with dopamine neurons (29) and the

dopamine response that has been observed is

modulated by opioids, it is likely that the effects

of cannabinoids on dopamine circuits involved in

reward are indirect and different from those of

drugs, such as cocaine and morphine that directly

affect dopamine levels and produce craving and

drug-seeking behavior (29). Nonetheless, the

observation that the ability of animals to recognize the intoxicating effects of THC can be

mimicked by drugs that selectively activate the

THC receptor indicates that these effects are

mediated through the THC receptor (9,23).

Chronic administration—Tolerance readily

develops to the behavioral and pharmacological

effects of THC in both humans and animal

experimental models (2,5 1). In humans, tolerance

develops to the mood, memory, motor, and

performance effects of the drug (51). The mechanism of this tolerance is thought to be a desensitization of the THC receptor, perhaps by some

alterations in its interaction with the second

messenger (2,51).

Cessation of cannabinoid administration does

not give rise to an intense withdrawal syndrome

(2,51). Only a few animal studies show that any

withdrawal symptoms result. Changes that have

been observed include increased motor and grooming activity in rats, altered susceptibility to

convulsion induced by electric shock in mice, and

increased aggressiveness in monkeys (51). In

humans, withdrawal signs are relatively mild

(2,51) and consist of changes in mood and sleep,

increased imitability and restlessness, anorexia,

and mild nausea. As with all drugs the relative

intensity of the withdrawal syndrome is dependent on the quantity, frequency, and duration of

drug use. While a severe physical dependence

phenomenon is not associated with cannabis

withdrawal, the probability of developing a form

of craving is high (2). The mechanism for these

various withdrawal effects is unknown, but it is

likely related to the unmasking of the desensitized

receptors on drug cessation. Also, both the

tolerance and withdrawal phenomena may be

related to alterations in the as yet unidentified

endogenous neurotransmitter that interacts with

the THC receptor (5 1).

| Lysergic Acid Diethylamide

Lysergic acid diethyklamide (LSD) is one of a

broadly defined class of drugs known as psychedelics. Other psychedelics include mescaline and

psilocybin. The effects of the psychedelics are

similar, but LSD is the most potent (13). These

drugs distort the perception of space and time, and

produce exaggerated sensory phenomena in vision, hearing, and touch. The subjective effects

associated with psychedelic use are strongly

determined by a number of factors such as setting,

expectations, user’s personality, and dose. In
Chapter 3-The Neuropharmacology of Drugs of Abuse | 35

some cases, adverse psychiatric effects occur

including ‘bad trips’, panic reactions, and even

psychotic episode during intoxication. While

these drugs are some of the most powerful

psychoactive drugs known and can have adverse

consequences, their dependence potential, as

measured by their reinforcing properties and

neuroadaptive response, is low as compared with

the other drugs discussed in this report. Psychedelic use has undergone cycles of popularity, such

as during the 1960s, and serves as an example of

how extrinsic societal factors can affect drug use,

in addition to the intrinsic pharmacological actions of a drug.

Acute administration—LSD’s psychedelic

properties are a result of its actions on the

serotonin neurotransmitter system (1 1,26). LSD

is thought to stimulate the various receptor

subtypes for serotonin, and has particular potency

in activating the serotonin autoreceptor (3). A

similar activation of the serotonin system is seen

with MDMA, which is a derivative of amphetamine and has both dopamine and serotonin

stimulating properties. Unlike LSD, MDMA

stimulates serotonin neurotransmission by blocking its reuptake into the presynaptic terminal (l).

This action on serotonin gives MDMA psychedelic properties in addition to its amphetaminelike stimulating properties. To date, no evidence

confirms that LSD supports self-administration in

animal studies (13).

Chronic administration—Tolerance develops rapidly to LSD and other psychedelics when

they are repeatedly administered and the extent of

the tolerance is greater than what is observed with

other drugs such as PCP or alcohol (13). The

mechanism of LSD tolerance is unclear. Since

LSD stimulates serotonin receptors and a typical

response of receptors to continued activation is a

desensitization process, it is possible that serotonin receptor desensitization plays a role.

Currently, there is no evidence that a withdrawal syndrome is associated with termination

of chronic hallucinogen use (13). The phenomenon of flashbacks, in which the perceptual changes

associated with LSD spontaneously appear after

drug cessation, are reported to occur in about 23

percent of regular users (31). It unclear whether

flashbacks represent a withdrawal syndrome and

are related to, or predictive of, hallucinogen

dependence (13).

SUMMARY

Studies of the pharmacological actions of drugs

of abuse indicate that their reinforcing properties

may be due to actions on a common neural circuit.

While the mechanisms involved for all drugs of

abuse have not been completely described, many,

either directly or indirectly, activate MCLP. Such

drugs include cocaine, amphetamines, opiates,

sedatives, and nicotine. For other drugs of abuse

the precise relationship, if any, to the brain reward

system is unclear.

Repeated administration of all drugs of abuse

is associated with neuroadaptive responses. In

general, tolerance develops to at least some of

their effects although the specific details of the

biological mechanisms underlying these changes

are not completely understood. In terms of

promoting substance abuse, an important action is

the development of tolerance to the reinforcing

properties of a drug. Available evidence suggests

that tolerance develops to the reinforcing properties of cocaine, alcohol, PCP, and opiates. A

withdrawal syndrome is associated with most

drugs of abuse, though the severity varies. Barbiturates, alcohol, stimulants, opiates, and benzodiazepines produce pronounced and sometimes

severe withdrawal symptoms, while those for

nicotine and caffeine is less intense. A mild

withdrawal is associated with cannabis use; while

there is no evidence of a withdrawal syndrome

related to LSD. Certain aspects of withdrawal,

such as changes in mood and motivation, induced

by the chronic drug state may be key factors to

relapse and drug-seeking behavior.
36 I Biological Components of Substance Abuse and Addiction

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_-—

Genetics 4

w

hy does one person become dependent on drugs while

another, exposed to the same environment and

experiences, does not? As progress in understanding

the role of genetics in various conditions and diseases

increases, there has been a realization that there is likely to be a

genetic component to substance abuse and addiction. That is,

inherited differences among individuals affect their response to

drugs. To date, much of the work done in this field is related to

alcoholism, less is known about the genetics of other drugs of

abuse.

Studies in both humans and animals contribute to the

understanding of genetic factors in substance abuse and dependence. Human studies shed light on the question of whether drug

dependency is transmitted between generations. In addition, the

study of individuals with substance abuse problems as well as

animal studies provide information about what is actually

inherited. For example, are there genetic differences in sensitivity and responsiveness to drugs? And, if yes, are the differences

drug-specific, or are they related to general mechanisms associated with the actions of all abused drugs? Finally, the tools of

modern molecular biology can be used to identify the specific

genes that control various cellular and biochemical functions

possibly involved in an inherited component of substance abuse

and addiction.

While the existence of inherited differences seems likely, a

genetic component alone probably is insufficient to precipitate

substance abuse and addiction. Unlike disorders such as Huntington’s disease and cystic fibrosis, which result from the

presence of alterations in a single gene, substance abuse is likely

39
40 | Biological Components of Substance Abuse and Addiction

to involve multiple genes that control various

aspects of the biological response to drugs. In

addition, the complex nature of drug dependency,

involving many behavioral and environmental

factors, indicates that any genetic component acts

in consort with other nongenetic risk factors to

contribute to the development of substance abuse

and addiction. Thus, neither the presence nor

absence of a genetic factor ensures development

of, or protection from, drug addiction.

DO INHERITED FACTORS EXIST?

A number of confounding factors complicates

the study of genetic transmission of substance

abuse liability in humans. One is the high

incidence of psychiatric conditions among substance abusers (104), which raises questions

about the role of psychiatric comorbidity in

liability to illicit drug addiction. In particular,

antisocial personality disorder (ASPD) is often

associated with substance abuse. One study

shows that 84 percent of individuals with ASPD

also have some form of substance abuse during

their lifetimes (104). Other psychiatric conditions

that may be associated with substance abuse are

depression, anxiety disorders, manic-depression,

and schizophrenia.

Another issue related to studies of the genetics

of liability to abuse of specific drugs is that many

drug abusers engage in multiple drug use, so examining any familial trends in the use of a particular

drug becomes difficult. Finally, rates of illicit

drug use show strong secular trends. Even assuming a vulnerability to drug-specific addictions,

there might be tremendous variations in expression of addiction, simply because of differences

in drug availability over time: No matter how vulnerable an individual might be, addiction requires

exposure. Such issues often hamper studies on the

genetic transmission of drug liability.

I Family Studies

ALCOHOLISM

References to a familial tendency or hereditary

‘‘taint’ of alcoholism date back to classical times

(44); an observation repeatedly confirmed by

family studies. While not all cases axe familial,

the risk of alcoholism consistently has been found

to be higher among frost-degree relatives (i.e.,

parents, siblings, children) of alcoholics as compared to the general population (79). Moreover,

while family studies can establish that a disorder

(or liability to a disorder) is transmitted; in

general, they are unable to distinguish between

biological and cultural transmission (though this

issue can be evaluated in large family studies by

analyzing multiple classes of relatives with differing degrees of genetic relatedness).

Results of numerous family studies indicate

that alcoholism segregates within families, with

male first-degree relatives of alcoholics having a

higher incidence (ranging from 27 to 54 percent)

than female first-degree relatives (6 to 17 percent)

as compared to first-degree relatives of nonalcoholics (20 percent of males, 4 percent of females)

(49,103,133). In fitting models of inheritance to

family data, researchers concluded that observed

patterns of inheritance were consistent with the

hypothesis that familial factors predisposing to

alcoholism were the same in men and women, but

that nonfamilial environmental factors exerted

more influence in the development of alcoholism

in women (20). Familial alcoholics (those with at

least one relative with alcoholism) appear to have

earlier onset, more antisocial symptoms, more

social complications of alcohol use, and worse

treatment outcome than nonfamilial alcoholics

(38,93,111).

Familial is not identical to genetic, and in the

case of alcoholism, the familial patterns of

inheritance are not consistent with those of a

purely genetic condition (58,109). In addition,

evidence suggests that the transmissibility of

alcoholism has increased over time (102). Thus,

any genetic factors promoting the development of
Chapter 4-Genetics | 41

alcoholism are significantly

genetic influences.

OTHER DRUGS

moderated by nonFewer family studies have been conducted on

the genetic transmission of liability to other drugs

of abuse. Nonetheless, the evidence available

suggests that, as in the case of alcohol, addiction

to other psychoactive substances appears to run in

families.

One study found evidence for familial aggregation of drug use, based on family history obtained

from individuals admitted for substance abuse

treatment (78). However, this study also combined use of all illicit drugs into one category and

relied on self-reports by the subject on his or her

drug use as well as that of family members. In a

large family interview study comparing 201

opiate addicts and 82 normal controls, as well as

interviews of 1,398 first-degree relatives of these

‘subjects, the relatives of opiate users had elevated

rates of drug addiction as compared with the

controls (105). In addition there was an association between opiate use and the presence of

ASPD. Further analysis of these data revealed

that the incidence of both drug abuse and ASPD

was higher among the siblings of the opiate

subjects than among their parents (69,70).

Some studies note a familial association between opiate addiction and alcoholism (65).

However, another family history study (51),

comparing families of 32 alcoholics, 72 opiate

addicts, and 42 individuals addicted to both

substances, found that while both opiate addiction

and alcoholism clustered within families, cooccurrence of the disorders within families occurred no more frequently than expected by

chance, thus supporting the hypothesis of independent transmission. However, a later study of

201 opioid addicts and 877 of their first-degree

relatives also showed familial aggregation of both

alcoholism and depressive illness suggesting a

possible co-occurence of the disorders (64).

Little research has been done to test hypotheses

regarding familial transmission of liability to

addiction to specific substances other than opiates

or alcohol. One study involving 350 treated drug

abusers and 1,478 relatives, found that alcoholism

was equally common among relatives of individuals who preferentially abused opiates, cocaine,

or sedative-hypnotics (27 percent, 31 percent, and

24 percent of male relatives, respectively), whereas

relatives of sedative-hypnotic users were subject

to diagnoses of other substance abuses (2 percent

of male relatives, versus 11 percent of male

relatives of opiate abusers and 16 percent of male

relatives of cocaine abusers) (80).

I Twin and Adoption Studies

While family studies can establish that a

disorder (or liability to a disorder) runs in a

family, they generally are unable to distinguish

between biological and cultural transmission.

However, two other methods are used to help

disentangle the effects of genetic and nongenetic

factors. Adoption studies compare the presence of

a trait among biological versus adoptive family

members or other control groups. In this way

individuals that share the same environment but

different genetic heritages, or vice versa, can be

compared. Twin studies, by contrast, involve

siblings raised in the same environment, but

compare how often identical twins, who are

genetically identical, and fraternal twins,1 who

are not, are similar, or concordant, for a trait. A

high concordance rate for a trait among identical

twins versus fraternal twins usually indicates a

genetic component for the trait.

TWIN STUDIES

Evidence fromn twin studies suggests genetic

influences on ‘ drinking patterns as well as alcoholrelated problems. Results from twin studies

demonstrate genetic influences on measures of

alcohol consumption such as abstention, average

1 Fraternal twins share the same in utero environment but are genetically no more similar than any two siblings,
42 | Biological Components of Substance Abuse and Addiction

alcohol intake, and heavy alcohol use (50,60,92).

Twin studies also indicate an inherited risk for

smoking (24).

When evaluating how alcoholism develops,

twin studies generally support the existence of

genetic influences on the development of the

disorder. One study found a higher concordance

rate for alcohol abuse between identical twins (54

percent) versus fraternal twins (28 percent) (57),

while two subsequent studies found no such

relationship (48,92,). A 1991 study (94) examined

50 male and 31 female identical twin pairs and 64

male and 24 female fraternal twin pairs, with 1

member of the pair meeting alcohol abuse or

dependence criteria. The study found that identical male twins differed fromn fraternal male twins

in the frequencies of both alcohol abuse and

dependence as well as other substance abuse

and/or dependence. On the other hand, female

identical and fraternal twins were equally likely to

abuse alcohol and/or become dependent on other

substances, but identical female twins were more

likely to become alcohol dependent. Another

study of 356 twin pairs also found higher identical

than fraternal rates of concordance for problems

related to alcohol and drug use as well as conduct

disorder (77). The same study also noted that

among men, heritability was greater for early

rather than late onset of alcohol problems, whereas

no such effect was seen for women. Finally, a

study of 1,030 female twin pairs found evidence

for substantial heritability of liability to alcoholism, ranging from 50 to 60 percent (61).

Thus, twin studies provide general agreement

that genetic factors influences certain aspects of

. . drinking. Most twin studies also show genetic

influence over pathological “ drinking, including

the diagnosis of alcoholism, which appears (like

many psychiatric disorders) to be moderately

heritable. Whether genetic factors operate comparably in men and women, and whether severity of

alcoholism influences twin concordance is less

clear. How psychiatric comorbidity may affect

heritability of alcoholism also remains to be

studied.

ADOPTION STUDIES

Adoption studies have supported the role of

heritable factors in risk for alcoholism (1 1,18,1 17).

The results from a series of studies conducted in

Denmark during the 1970s are typical. Of 5,483

nonfamily adoption cases from the copenhagen

area between 1924 and 1947, the researchers

studied 55 male adoptees, and later compared 20

adoptees with 30 nonadopted brothers. They also

studied 49 female adoptees, comparing them with

81 nonadopted daughters of alcoholics. Comparisons also were made with matched control

adoptees. The Copenhagen study revealed that

adopted-away sons of alcoholic parents were four

times as likely as adopted-away sons of nonalcoholics to have developed alcoholism; evidence

also suggested that the alcoholism in these cases

was more severe. The groups differed little on

other variables, including prevalence of other

psychiatric illness or “heavy drinking.” Being

raised by an alcoholic biological parent did not

further increase the likelihood of developing

alcoholism. That is, rates of alcoholism did not

differ between the adopted-away children and

their nonadopted brothers. In contrast, daughters

of alcoholics were not at elevated risk of alcoholism. Among adoptees, 2 percent had alcoholism

(and another 2 percent serious drinking problems), compared with 4 percent of alcoholism

among the adopted controls and 3 percent among

nonadopted daughters (44).

Another analysis examined factors promoting

drug abuse as well as alcoholism (17). In this

study, all classes of illicit drug use were collapsed

into a single category of ‘‘drug abuse. ” Most of

the 40 adopted drug abusers examined had

coexisting ASPD and alcoholism; the presence of

ASPD correlated highly with drug abuse. Among

those without ASPD, a biological background of

alcoholism (i.e., alcoholism in a biological parent) was associated with drug abuse. Also,

turmoil in the adoptive family (divorce or psychiatric disturbance) was also associated with increased odds for drug abuse in the adoptee.
Chapter 4-Genetics |43

Finally, results from other adoption studies

suggest two possible forms of alcohol abuse

(12,19). The two forms have been classified as

“milieu-limited” or type 1 alcohol abuse and

“male-limited” or type 2 alcohol abuse (21).

Type 1 alcohol abuse characterized by mild

alcohol problems and minimal criminal behavior

in the parents, is generally mild, but occasionally

severe, depending on presence of a provocative

environment. Type 2 is associated with severe

alcohol abuse and criminality in the biological

fathers. In the adoptees, it was associated with

recurrent problems and appeared to be unaffected

by postnatal environment.

I n summary, adoption studies of alcoholism

clearly indicate the role of biological, presumably

genetic, factors in the genesis of alcoholism. They

do not exclude, however, a possible role for

nongenetic, environmental factors as well. Moreover, evidence suggests more than one kind of

biological background conducive to alcoholism.

In particular, one pattern of inheritance suggests

a relationship between parental antisocial behavior and alcoholism in the next generation. Thus,

adoption studies, like other

even at the genetic level,

homogeneous construct.

designs, suggest that

alcoholism is not a

WHAT IS INHERITED?

Although studies indicate that genetics contributes to alcoholism and probably other drug abuse,

they lack information about what exactly is

inherited. For example, do individuals with a

family history of drug abuse have an increased

susceptibility or sensitivity to the effects of drugs

with reinforcing properties? If a susceptibility

exists, what are the biological mechanisms that

underlie it? To understand what might be inherited, both individuals who have a substance abuse

problem and animals models of substance abuse

are studied. Various types of information can be

derived from these studies. As with family, twin,

and adoption studies, much more information is

available about alcoholism as compared with

other drugs of abuse.

First, specific inherited risk markers for alcoholism and other substance abuse can be identified. A risk marker is a biological trait or

characteristic that is associated with a given

condition. Thus, if an individual is found to have

an identified marker for substance abuse, he or

she is at risk for developing a drug dependency.

To date, no biological characteristic has been

clearly identified as being a risk marker for either

alcoholism or substance abuse, although evidence

suggests some possible candidates. The identifcation of a valid and reliable risk marker could

provide important information about the fundamental mechanisms underlying substance abuse

and addiction and would be an invaluable aid in

diagnosis and treatment.

Second, inherited differences in biochemical,

physiological, and anatomical processes related

to differences in drug responses might be identified and studied. Thorough biological assays can

be performed using animal models of substance

abuse. Animal models of substance abuse consist

of strains of animals (usually rodents) that have

been selectively bred to either exhibit a preference for taking a drug, exhibit a preference for not

taking a drug, or differ in some way in their

behavioral or physiological response to a drug.

Thus, such differences represent inherited traits

related to drug-taking behavior, and these animals

can be studied to determine what biological

mechanisms are involved in the expression of

such traits.

Finally, the genetic technique of linkage analysis can narrow the area on a chromosome where

a gene may be located. It can lead to the

identification of the gene itself, which, in turn,

can improve the understanding of the molecular

events that underlie the expression of the gene.

There have been few genetic linkage studies

related to substance abuse since few specific

biological traits associated with drug dependency

have been identified. Some studies in humans

have been carried out related to alcoholism but the
44 I Biological Components of Substance Abuse and Addiction

findings of these studies are contradictory and

inconclusive (see later discussion).

Specific Risk Markers

ELECTROPHYSIOLOGICAL ACTIVITY

Attempts to correlate distinctive patterns of

spontaneous electrical activity of the brain with

alcoholism and substance abuse have been equivocal. A few studies have found distinctive electroencephalograph (EEG) patterns in individuals at

risk for alcoholism (32,39), but others have not

(31,59,101). Similarly, the use of alcohol challenge (i.e., giving the subject alcohol and then

recording EEG) on subjects at high risk for

alcoholism has likewise yielded inconclusive

results. The rationale for challenge studies rests

on the observation that alcohol has been shown to

affect resting EEG, and thus might have a

differential effect on those at low and high risk for

alcoholism (100). Again, some studies have seen

distinctive responses (100,101), while other have

not (39,59).

A logical extension of studying resting EEG

activity is examining event-related potentials

(ERPs). ERPs are patterns of brain electrical

activity produced in response to a particular

stimulus (e.g., auditory, visual); they can reflect

a variety of sensory and cognitive processes.

Since ERPs may reflect heritable differences in

cognitive function or capability that may in turn

contribute to liability to alcoholism, some have

suggested that ERP changes may allow discrimination between those at low and high genetic risk

for alcoholism. The results of these studies have

also been equivocal. Some have found characteristic responses among individuals at risk for

alcoholism (3,4,33,52,53,89,90,125) while others

have not (95,96,97,98). In addition to being

equivocal, the specificity for alcoholism of such

findings is unclear. In particular, it is not yet

known whether similar findings might be identified in subjects with (or at risk for) illicit drug

abuse.

Currently, both EEG

best viewed as possible

and ERP findings seem

markers. Further studies

are needed to confirm or refute the positive results

that have been observed. In addition, while ERP

findings in particular might relate to aspects of

sensory, perceptual, or cognitive functioning that

may differ among those at risk for alcoholism,

how such differences contribute to risk for

alcoholism and perhaps substance abuse is not

well understood.

BIOCHEMICAL ASSAYS

Serotonin—Results over the last two decades

from both human and animal studies have supported a relationship between low levels of

central nervous system (CNS) (i.e., brain and

spinal cord) serotonin and impulsive and violent

behavior (130,131). Since problematic use of

alcohol (as well as other drugs) has long been

associated with a wide range of violent behavior,

scientists have examined the relationship between alcoholism and serotonergic abnormalities.

While a consistent relationship between alcoholism and low CNS levels of serotonin and its

metabolizes is lacking, mounting evidence supports the presence of such abnormalities in a

subgroup of alcoholics with early-onset problems

and a history of violence (16,67,68,107,130).

Because measures of serotonin activity are

difficult to obtain, researchers have used pharmacologic probes of serotonin function, such as

hormonal response to drugs that affect serotonin.

These indirect measures have also indicated a

relationship between impulsivity, substance abuse,

and abnormal serotonin function (37,42,71,83).

For alcoholism, given that early-onset alcoholism and ASPD overlap substantially (16), the

specificity of the serotonin findings is unclear,

especially as similar results have been found in

substance abusers with ASPD (71). However, at

least one report has indicated that, even after

controlling for the presence or absence of ASPD

and illicit drug abuse, other neurochernical findings remained significantly associated with alcoholism (106). While further work might delineate
Chapter 4-Genetics| 45

the relationship between decreased CNS serotonin levels and Specific psychiatric syndromes,

current evidence suggests relatively specific biological differences may exist between early- and

late-onset alcoholics; raising the possibility of

defining biologically homogeneous subgroups.

Aldehyde and alcohol dehydrogenase enzymes-Many Asians rapidly develop a prominent facial flush following ingestion of a small

amount of alcohol. Continued drinking leads to

nausea, dizziness, palpitations, and faintness.

This reaction is due to inactivity in individuals’

aldehyde dehydrogenase, an enzyme that helps

metabolize (i.e., break down) alcohol in the body.

Ineffective enzyme activity results in a buildup of

the chemical acetaldehyde in the blood following

alcohol consumption. Clinicians have taken advantage of the aversive properties of acetaldehyde

buildup by using the drug Antabuse to inhibit

aldehyde dehydrogenase, thus inducing a severe

form of the adverse reaction in abstinent alcoholics who begin to drink (30,135).

Alcohol dehydrogenase is another enzyme

involved in the metabolism of alcohol. A mutant

form of alcohol dehydrogenase also produces a

transient increase in the acetaldehyde concentration after alcohol ingestion. This form of the

enzyme also has been reported in Asian populations.

The two enzymes, aldehyde and alcohol dehy -

drogenase, probably interact in some individuals

to amplify the adverse reaction to alcohol consumption (129). Since this reaction discourages

heavy “drinking, the observation that it commonly

occurs in some populations where alcoholism is

relatively rare suggests that alcohol and aldehyde

dehydrogenase mutations might be a major determinant of alcohol consumption, abuse, and dependence. This would seem to hold true for

Taiwan and Japan where the reaction occurs in 30

to 50 percent of individuals.

The genetics of the aldehyde and alcohol

dehydrogenases are well described. The production of the different forms of these enzymes is

caused by variations of their normal genes. The

presence of these gene variations in an individual

accounts for variations in the metabolism of

alcohol (54). Thus, the presence of these genes

can also effect alcohol consumption. For example, the gene variations that code for the ineffective form of aldehyde dehydrogenase is not only

less common in alcoholics, but also is rare in

Japanese patients with alcoholic liver disease

(27, 121,135). Despite identification of such genes,

the relationship between their inheritance and the

familial transmission of alcoholism remains unstudied.

Alcohol challenge-A number of studies have

been conducted investigating the effect of administering alcohol to young adult sons of alcoholics

(99). These studies indicate that, despite similarity of blood alcohol levels, sons of alcoholics

demonstrate less intense subjective responses to

alcohol, as well as less intense upper body sway

(110,111,113,114). Thus, one mechanism by

which alcoholism might develop is that since

these individuals have less of a reaction to

alcohol, they would find it more difilcult to

self-regulate alcohol consumption, thus increasing the risk of developing dependence. In conjunction with these findings, other studies have

found that sons of alcoholics demonstrate slightly

lower levels of certain hormones (i.e., prolactin,

cortisol, adrenocorticotropin hormone (ACTH))

after ingesting alcohol as compared to controls

(82,1 14,115,116,1 18). The relationship, if any, of

these decreased hormonal levels to alcohol consumption is unclear.

COGNITIVE DIFFERENCES

Study of high-risk populations (e.g., sons of

alcoholics) has revealed temperamental, as well

as biological, differences between high-risk and

control subjects, leading to the suggestion that

vulnerability to alcoholism can be conceptualized

from a behavior-genetic perspective (127). Heritable, constitutional differences, in other words,

might affect temperament and, hence, risk for

alcoholism and addiction to other drugs. In

particular, these differences might influence cog-
46 | Biological Components of Substance Abuse and Addiction

nitive styles, learning ability, and capability to

control one’s own behavior.

In general, it appears that sons of alcoholics

demonstrate group differences from low-risk

populations in that the former tend to have

impairment on tests of cognitive development,

academic achievement, and neuropsychological

function (34,12,8). However, the magnitude of

these differences may depend greatly on how the

population is ascertained. To date, little is known

of what specific psychological, temperamental, or

cognitive factors might distinguish between highrisk subjects who actually go on to develop

alcoholism from those who do not (128).

I Biological Mechanisms

. Animals that have been bred for specific

characteristics are a valuable tool in drug use and

abuse research. For example, certain strains of

rodents differ in their response to the analgesic

and body temperature regulating effects of morphine, the motor activating effects of stimulant

drugs, and the convulsant producing properties of

benzodiazepines (28,122). Since the essential

characteristic of human drug abuse and addiction

is persistent drug-seeking behavior, the most

salient models are those of genetic differences in

drug self-administration and the factors associated with it (e.g., tolerance). While there are some

genetic models of self-administration or preference for different drugs (i.e., alcohol, opiates,

cocaine) (28,41), more information is available

about the hereditary biological mechanisms that

underlie the self-administration of alcohol than

other drugs.

ALCOHOL

A general working hypothesis is that alcoholics

are sensitive to the low-dose rewarding properties

of alcohol, are less sensitive to the high-dose

actions of ethanol (i.e., have a higher aversive

threshold) and develop tolerance to the aversive

effects of alcohol. The fact that rats can be

selectively bred to have such alcohol drinking

characteristics supports a genetic link to these

traits.

Dopamine and alcohol intake-Studies of

dopamine content in the brains of two different

strains of rats bred for either preference or

nonpreference for alcohol have found 25 to 30

percent lower levels of dopamine in the nucleus

accumbens and the olfactory tubercle of the

alcohol-preferring rats (45,74,86). No other differences in dopamine content have been observed

in other brain areas. These data suggest an

abnormality in the dopamine system projecting

from the ventral tegmental area to limbic regions

(nucleus accumbens and/or olfactory tubercle) of

the alcohol-preferring rats. Since this system is

thought to be involved in mediating the actions of

various drugs of abuse (see ch. 2) and alcohol is

thought to increase dopamine levels in the system

(see ch. 3), it may indicate that an abnormal

functioning of the mesocorticolimbic dopamine

system might be involved in promoting high

alcohol “ drinking behavior. That is, the alcohol

preference may be related to the ability of alcohol

to compensate for the abnormality. The nature of

this abnormality is unknown but may be due to

one or more of the following factors: decreased

dopamine synthesis, a lower number of dopamine

neurofibers, and/or reduced functional activity of

dopamine neurons.

Some evidence exists that the mesocorticolimbic dopamine system may respond to systemic

ethanol administration to a greater degree in the

alcohol-preferring strains than in the nonpreferring strains. Studies have found that levels of

dopamine metabolizes were higher in areas of this

system (i.e., caudate nucleus, medial prefrontal

cortex, and olfactory tubercle) after ingestion of

alcohol in alcohol-preferring rats as compared to

nonpreferring rats (35,36). Also, one study has

reported that the oral self-administration of alcohol, under experimental conditions where the

animal was allowed to receive alcohol as a reward

for performing a task, increased the synaptic

levels of dopamine significantly more in the

nucleus accumbens of these alcohol-preferring
rats than in nonpreferring rats (132). It was also

established that the alcohol-preferring strain of

rats will self-administer alcohol directly into the

ventral tegmental area (73,74). These studies

suggest that the mesocorticolimbic dopamine

system is involved in regulating alcohol drinking

behavior and that alcohol may be a stronger

positive reinforcer in alcohol-preferring rats than

in the nonpreferring rats.

Differences in dop amine receptor populations

have also been reported. Two genetically determined high-alcohol seeking lines of rats have

been reported to have fewer of one type of

dopamine receptor (i.e., the D2 receptor) in their

limbic system compared with the nonalcoholic

rats (74,124), Twenty percent fewer D2 receptors

were observed in the olfactory tubercle and

nucleus accumbens of these rats. These studies,

along with genetic linkage studies (see later

discussion), provide support for the involvement

of the D2 receptor in alcohol-preference.

Serotonin and alcohol intake--Examination

of alcohol-preferring and nonpreferring rats has

indicated a relationship between high alcohol

preference and a deficiency in the CNS serotonin

system. A number of studies have reported 10 to

30 percent lower levels of serotonin and its

metabolizes in the brains of alcohol-preferring

rats as compared with alcohol nonprefening rats

(45,66,74,84,85,86). Only one study, using a

strain of rats not used in any of the others, did not

find lower brain serotonin levels (63). Areas of

the brain found to have low serotonin levels

include the cerebral cortex, frontal cortex, nucleus accumbens, anterior and corpus striatum,

septal nuclei, hippocampus, olfactory tubercle,

thalamus, and hypothalamus.

Since several of these CNS regions may be

involved in mediating the rewarding properties of

drugs of abuse, including alcohol, these findings

suggest a relationship between lower contents of

serotonin in the brain and high alcohol preference.

Evidence suggests that the serotonin system is

involved in regulating the activity of the dopamine mesocorticolimbic system ( 136). Also, some

. . . . . . . . -- — .

Chapter 4-Genetics | 47

of the areas found to have low serotonin levels

(i.e., hypothalamus, hippocampus) may be involved in mediating the aversive effects of

alcohol. Since the development of tolerance to the

aversive actions of alcohol is one possible characteristic of alcoholic abuse, a deficiency in serotonin in these areas may be an innate factor

promoting tolerance to the aversive effects of

ethanol in alcohol-preferring lines of rodents.

Further study of one of the rat strains used in

these studies showed that low serotonin in the

alcohol-preferring line compared with the nonpreferring line was due to fewer serotonin containing axons (137). This study found fewer

serotonin presynaptic fibers forming synapses in

the nucleus accumbens, frontal cortex, cingulate

cortex, and hippocampus of alcohol-preferring

rats. These results suggest that the low serotonin

is the result of structural differences in the CNS

serotonin system rather than lower production of

serotonin. Examination of this same strain of rats

found that there were increased numbers of one

type of post-synaptic serotonin receptor in areas

of the frontal cortex and hippocampus (73,76,134).

This increase in the number of serotonin postsynaptic receptors may represent a compensation for

the lower number of presynaptic serotonin fibers.

No such increase in receptors was found in the

strain of rats with normal levels of brain serotonin

activity discussed earlier (62).

Overall, the animal data favors an inverse

relationship between the functioning of the CNS

serotonin system and alcohol drinking behavior.

Thus, innate low functioning of the serotonin

system may be associated with high alcohol

preference. In support of this concept, some

studies have found lower cerebrospinal fluid

serotonin metabolize concentrations in alcoholics

than in various control populations (2,14).

GABA and the actions of alcohol—Evidence

indicates that alcohol can exert some of its

antianxiety and intoxicating effects by potentiating the actions of the neurotransmitter gamma

amino butyric acid (GABA) at the GAB AA

receptor (see ch. 3) and that this receptor might be
48 I Biological Components of Substance Abuse and Addiction

involved in mediating alcohol drinking behavior

of alcohol-preferring rats (75). However, little has

been published that indicates an innate abnormality may exist in the GABA system that could be

associated with alcohol preference. A recent

study examined the densities of GABA containing fibers in the nucleus accumbens and other

brain areas of two different strains of alcoholpreferring and nonprefering rats (55). The results

of this study indicated a higher density of GABA

fibers in the nucleus accumbens of the alcoholpreferring rats compared with the nonpreferring

rats. There were no differences between the

respective lines in the other regions. These results

suggest alcohol preference may involve an innate,

abnormal GABA system within the nucleus

accumbens.

The experimental drug RO 15-4513 binds to

the GABAA-BDZ-Chloride channel receptor complex (see ch. 3) and is known to block the actions

of alcohol at this receptor (126). The administration of RO 15-4513 reduced alcohol but not water

intake in a study using one of the alcoholpreferring line of rats (75). The blocking effect of

RO 15-4513 on alcohol intake could itself be

blocked by administration of a drug that blocks

the benzodiazepine receptor. These results indicate that the GABAA

-BDZ-chloride channel receptor complex may be involved in mediating the

reinforcing actions of ethanol that promote alcohol drinking behavior in these rats. The observation that RO 15-4513 blocks oral self-administration of alcohol supports this idea (56,108).

Furthermore, treatment with a drug that activates

the GABAA receptor was shown to markedly

increase the acquisition of voluntary ethanol

consumption in laboratory rats (123). Also,

GABAA receptor function is enhanced by alcohol

in animals selected for sensitivity to alcohol

intoxication, but alcohol has little effect on

GABAA receptors of animals selected for resistance to alcohol intoxication (28). Overall, these

results are consistent with the involvement of the

GABAA receptor in regulating alcohol consumption. (See also ch. 3).

Alcohol withdrawal severity—Animal models have been developed for differential genetic

susceptibility to alcohol withdrawal. For example, withdrawal seizure-prone mice display a

higher incidence of convulsions than do seizureresistant mice when exposed to identical alcohol

concentrations (29). Other studies suggest that

this alcohol withdrawal reaction is mediated by

an increased sensitivity of channels for calcium

ions, coupled to receptors for excitatory amino

acids (46,47). Several results have emerged in

studies of these mouse lines that are potentially

important for understanding drug abuse. For

example, studies indicate that independent genetic factors control alcohol sensitivity, tolerance, and dependence, suggesting that these

features of drug abuse are maintained by different

neurobiological mechanisms (28). In addition, the

alcohol withdrawal seizure-prone mice have more

severe withdrawal to other depressant drugs (i.e.,

diazepam, phenobarbital, nitrous oxide) (6,7,8)

suggesting that a group of genes acts to influence

drug withdrawal severity not only to alcohol, but

also to a number of other depressant drugs.

OTHER DRUGS

A variety of strains of rats and mice has been

developed that exhibit genetic variations in their

sensitivity to the reinforcing effects of drugs of

abuse and in their drug-seeking behavior (28). In

addition, genetic differences in various biological

and neurochemical mechanisms have been observed in these animals.

For example, strains of rats and mice that differ

in their sensitivity to the reinforcing properties of

cocaine and in their cocaine-seeking behavior

have also been observed to have differences in the

number of dopamine containing neurons and

receptors in certain brain areas (120). While the

role of these biological findings in the expression

of the behavioral traits is unclear, given that

dopamine is the key neurotransmitter in cocaine’s

action, it is likely that a link may exist. Other

studies have shown that the development of

nicotine tolerance is genetically related. Strains of
Chapter 4-Genetics | 49

mice that differ in the rate at which they develop

tolerance to nicotine have also been found to

differ in nicotine receptor changes following

chronic administration of the drug (72). Thus,

inherited differences in nicotine receptor mechanisms may underlie inherited differences in the

development of nicotine tolerance.

A recent study indicates that inherited differences in the intracellular mechanisms of the

neurons in the mesocorticolimbic pathway could

contribute to a genetic predilection to drug

addiction (87). In a comparison of rats with either

high or low rates of self-administering drugs of

abuse, the higher self-administering strain exhibited differences in the intracellular mechanisms

that control activity in the neurons of the ventral

tegmental area and nucleus accumbens (5).

The further examination of causative relationships between inherited neurochemical alterations and inherited behavioral traits would produce valuable information about the biological

mechanism that underlies genetic factors related

to substance abuse and addiction. The recent

development of new and more sensitive techniques to analyze brain activity and processes will

facilitate such studies.

I Linkage Studies

Genetic linkage studies establish an association between an area of a specific chromosome

and the expression of a trait. Linkage analysis

uses specific markers that identify the area on a

chromosome that might contain the gene of

interest. If the marker consistently occurs in

association with the expressed trait, then it is

likely that the gene interest is in chromosomal

region.

In the area of substance abuse and addiction,

genetic linkage studies have purported to show a

linkage between the gene for the dopamine D2

receptor and alcoholism. The gene for the D2

receptor has two forms associated with two

markers, the A 1 and A2 alleles. The Al allele

occurs in about 20 percent of the population,

while the AZ allele is found in the remaining 80

percent (l). Two separate studies (9,10) reported

that the frequency of the Al allele for the D2

dopamin e receptor was significantly greater in

severe alcoholics compared with nonalcoholics.

Furthermore, another study (88) found that individuals with the Al allele had fewer D2 receptors

than those with the A2 allele. In agreement with

these findings, another study (91) observed a

significant association between the Al allele of

the D2 receptor and alcoholism. An association of

the Al allele with alcoholism and decreased

numbers of D2 dopamin e receptors implies a role

for an inherited deficit in the dopamine system in

alcoholism. However, in contrast to these results,

other studies have not found an association

between the frequency of the Al allele of the D2

receptor and alcoholism (13,26,40,1 19). The discrepancies between these studies has called into

question the validity of the association of the Al

allele with alcoholism.

Moreover, the report of a higher prevalence of

the Al allele not only in alcoholics, but also in

other disorders such as autism, attention deficit

hyperactivity disorder, and Tourette’s syndrome

(25), suggests that the presence of the Al allele is

not specific for alcoholism, but that it has a more

diffuse effect that can contribute to the occurrence

of other conditions. Also, recent findings indicate

that the frequency of the Al allele varies markedly among different populations (e.g., it is high

in some Native Americans) but there does not

appear to be an association with its increased

frequency and the occurence of alcoholism (43).

This complexity, coupled with the heterogeneous

and complex nature of alcoholism, could account

for the disagreements among these studies. Such

complexity makes construction of appropriate

control groups difficult, which in turn can affect

study results. Additional research is needed to

unravel the disagreement and establish the importance of these findings. It might be that the

presence of the Al allele is not unique to

alcoholism, but rather, causes a general alteration
50 I Biological Components of Substance Abuse and Addiction

in the brain dopamine system that then exacerbates or contributes to alcohol abuse.

SUMMARY

The existence of heritable influences on normal

and pathological consumption of alcohol is supported by results from family studies, twin

studies, and adoption studies as well as research

on animal models. Animal studies have established that alcohol preference and the reinforcing

actions of alcohol are influenced by genetic

factors. While there have been fewer studies

examining the genetic component of vulnerability to the addictive properties of other drugs of

abuse, evidence from animal studies supports a

genetic influence on the use and abuse of drugs

other than alcohol. The study of nonalcohol drug

abuse in humans is more difficult because of

substantially smaller populations that use or

abuse these drugs and marked changes in availability and, hence, exposure to these agents.

Investigation in this area is further hampered by

the complexity of subjects’ drug use: Most drug

abusers have used multiple agents. This has led

researchers either to concentrate on one class of

drug or to treat all illicit drug use as equivalent.

The tendency to lump all illicit drugs into one

category makes results difficult to interpret or

compare.

In the case of alcohol, studies indicate that low

doses of alcohol are stimulating and produce a

strong positive reward in animals susceptible to

the addictive properties of alcohol. Another

component of excessive alcohol consumption

might be that alcoholics have a high threshold to

the aversive effects of ethanol. This could be a

result of an innate low sensitivity to medium and

high doses of alcohol and/or acute tolerance to its

aversive effects. Results from animal studies

suggest an association between high alcohol

preference and acute tolerance to the medium-and

high-dose effects of ethanol. These animal experiments need to be extended and consideration

should be given to related studies in humans.

Findings with animals selectively bred for alcohol preference need to be extended to studies of

sensitivity, tolerance, and preference for other

drugs of abuse.

Neurobiological evidence points to common

pathways mediating the positive reinforcing actions of alcohol and other drugs of abuse. Most

evidence is consistent with the involvement of the

mesocorticolimbic dopamine system in drug reinforcement mechanisms. Other neuronal pathways

that regulate the activity of the mesocorticolimbic

dopamine system may also be involved in mediating the rewarding properties of ethanol and other

drugs of abuse. In the case of serotonin, innate,

genetically determined factors appear to reduce

CNS activity of serotonin, which is associated

with heavy alcohol drinking. In addition, animal

and human studies suggest an inherited difference

in dopamine response to alcohol consumption

and possibly an anomaly in the D2 receptor for

Dopamine associated with alcohol abuse. Additional studies with animals and humans are

needed to clarify these differences and to explore

the relationship of other neurobiological mechanisms related to the inherited components of other

drugs of abuse.

Alcoholism and drug abuse are complex conditions that are the result of multiple causal factors.

Alcoholism and other forms of addiction represent entities that have a genetic component but

require specific (but as yet poorly understood)

environmental influences to manifest. Thus, consideration of the impact of genetic factors must

also take into account general social conditions

such as availability and cost of substances,

acceptability of use, and specific environmental

influences on initiation of use, maintenance or

cessation of use, and development of use-related

problems. A major goal of addiction research in

clinical populations is to determine who is

vulnerable under what conditions. Understanding

this interaction might lead to better prediction of

relapse as well as improved matching of patients

and treatments.
Chapter 4-Genetics 151

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Appendix A:

The Drug Evaluation

Committee of the

College on Problems

of Drug Dependence

The Comprehensive Drug Abuse Prevention and

Control Act (PL 91-513) and the Psychotropic Substances Act of 1978 (PL 95-633) gives exclusive

authority to the Secretary of the Department of Health

and Human Services to determine the abuse liability of

substances and to make recommendations concerning

their regulation and other drug policy decisions.

Although the Secretary receives advice from the Drug

Enforcement Agency (DEA), the Food and Drug

Administration (FDA), and various other regulatory

agencies, these laws explicitly state that the National

Institute on Drug Abuse (MDA) must provide to the

secretary information relevant to the abuse potential of

suspected drugs of abuse and all information relevant

to an assessment of their abuse potential. On the basis

of this information from NIDA, and information from

FDA and DEA, the secretary makes a judgment as to

the dependence potential of new drugs.

NIDA’s role in providing information relevant to

the dependence liability of potential substances of

abuse has placed enormous demands on the Institute.

The agency supports a variety of activities in commercial and private laboratories around the country to

provide this information. One of its principal sources

of information comes from the College on Problems of

Drug Dependence (CPDD) and, specifically, its Drug

Evaluation Committee (DEC). The relationship between NIDA and CPDD is both formal and informal:

NIDA provides over 98 percent of the funds required

to assess the dependence liability of compounds in

CPDD-sponsored testing facilities, NiDA is an official

liaison member of CPDD, and CPDD provides direct

input as requested in all NIDA decisions regarding the

dependence potential of drugs.

Established in 1929, CPDD is the longest standing

group in the country concerned with drug dependence

and abuse. It is an independent body, affiliated with

most scientific societies concerned with the dependence potential of abused substances and with regulatory and governmental agencies such as the World

Health Organization (WHO), MDA, the National

Institute on Alcoholism and Alcohol Abuse, DEA, and

FDA. Each of these agencies has formal ties with

CPDD via liaison membership. In turn, CPDD provides liaison representation to FDA and all other

agencies on request.

CPDD has three major functions: to assess the abuse

liability of psychoactive drugs; to hold an annual

scientific meeting to review the status of the dependence liability of drugs; and, to seine as a consultant to

the private sector and various governmental agencies

on all drug-related matters and policies.

DEC oversees all aspects of CPDD’S dependence

liability testing program. DEC is devoted to research

on drugs of abuse and the determination of the

dependence potential and abuse liability of specific

classes of drugs: analgesics, stimulants, and depressants. Governmental and regulatory agencies, such as

NIDA, DEA, and FDA have relied on DEC for

information on the abuse liability of opiate-like

compounds and stimulant and depressant drugs, In

addition, CPDD is a collaborating center to WHO and

provides information about the abuse potential of

pharmaceuticals and scheduling worldwide. Producing this information is generally beyond the capabili59
60 I Biological Components of Substance Abuse and Addiction

ties of third world countries. Finally, CPDD provides

the pharmaceutical industry and academic investigators information on new and novel compounds in the

design and development phase. Thus, the information

provided plays an important role in scheduling drugs,

drug policy making decisions, and the facilitation of

new drug development.

Approximately 50 to 60 drugs per year are submitted by industry, academic institutions, National Institutes of Health (NIH) laboratories, NIDA, WHO, and

DEA (generally as a result of confiscation). A computerized list of submitted compounds is maintained at

NIH; the code is broken only when testing is complete

testing.

Appropriate quantities of the compounds are

distributed for testing to the various laboratories that

work under the auspices of CPDD. The test results are

released as soon as practical, but at most within 3 years

of receipt of the compound. Information about the

drugs is confidential until one of three conditions is

satisfied: the submittee grants explicit permission to

release the data; 3 years have elapsed or, Federal

and/or regulatory organizations request CPDD to

provide information concerning the compound for the

public welfare (e.g., a determination of whether the

compound should be scheduled under the Controlled

Substances Act prior to its marketing and distribution

to humans).

Two university-based groups are involved with

DEC’S evaluation of the analgesic types of drugs, and

three with evaluation of the stimulants and depressants. The Medical College of Virginia, Virginia

Commonwealth University, and the University of

Michigan Medical School examine analgesics, using

different methods to discern the physical dependence

potential and abuse liability of presumed analgesics.

Those two academic centers, along with the Mississippi Medical Center test stimulants and depressants.

‘The programs’ testing determines dependence liability of drugs and, on request, carries out more

detailed studies to examine specific aspects of dependence liability, such as tolerance. For the last 30 years,

this program has been largely responsible for obtaining

basic scientific information on specific classes of

compounds and the mechanisms involved in their

acute and chronic pharmacological effects. DEC

receives new compounds that are generally unavailable to other testing groups and provides scientific data

on the pharmacology and abuse potential of new

compounds. Thus the program contributes to the

development of new drugs and the understanding of

the mechanisms

drugs.

underlying the abuse liability of
Appendix B

Acknowledgments

OTA thanks the members of the advisory panel, contractors, and the many individuals and organizations that

supplied information for this report, In addition, OTA acknowledges the following individuals for their comments

on drafts of this report:

Mary Abood

Virginia Commonwealth University

Richmond, VA

Martin Adler

Temple University School of Medicine

Philadelphia, PA

Robert Balster

Virginia Commonwealth University

Richmond, VA

Henry Begleiter

State University of New York

Brooklyn, NY

John Crabbe

Department of Veterans Affairs Medical Center

Portland, OR

Stephen Dinwiddie

Jewish Hospital of St. Louis

St. Louis, MO

Stephen Dworkin

Wake Forest University

Winston-Salem, NC

Linda Dykstra

University of North Carolina

Chapel Hill, NC

R. Adron Harris

University of Colorado Health Sciences Center

Denver, CO

Kenneth M. Johnson

University of Texas Medical Branch

Galveston, TX

William McBride

Institute of Psychiatric Research

Indianapolis, IN

Herman H. Samson

Wake Forest University

Winston-Salem, NC

William Woolverton

University of Mississippi Medical Center

Jackson, MS

61
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 GPO Deposit Account

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(Additional address\attention line) ❑ VISA orMasterCard Account

I

1

(Street address)

I

1111 1

(Credit card expiration date) Thank you for

(City, State, ZIP Code)

your order!

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Mail To: New Orders, Superintendent of Documents, P.O. Box 371954, Pittsburgh, PA 15250-7954

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Superintendent of Documents Publications Order Form

Order Processing Code: P3

“7200 Telephone orders (202) 783-3238

To fax your orders (202) 512-2250

❑ YES, please send me the following: Charge your order.

/t’s Easy!

copies of Biological Components of Substance Abuse and Addiction-Background Paper (68 pages),

S\N 052-003 -01350-9 at $4.25 each.

The total cost of my order is $ . International customers please add 25%. Prices include regular domestic

postage and handling and are subject to change.

Please Choose Method of Payment:

(Company or Personal Name) (Please type or print) Check Payable to the Superintendentof Documents

❑ GPO Deposit Account ~ ’ n

(Additional address/attention line) ❑ VISA orMas~erCardAccoUnt

(Street address) 1111111111111111111 H

11111(Credit card expiration date) Thank you for

(City, State, ZIP Cwie)

your order!

(Daytime phone including area code) (Authorizing Signature) (9/93)

(Purchase Order No.) YES NO

May we make your name/address available to other mailers?n ❑

Mail To: New Orders, Superintendent of Documents, P.O. Box 371954, Pittsburgh, PA 15250-7954

THIS FORM MAY BE PHOTOCOPIED