U.S. Department of Health

& Human Services

National Institutes of Health

National Institute on Alcohol Abuse

and Alcoholism

Number 77 April 2009

NEUROSCIENCE:

PATHWAYS TO ALCOHOL

DEPENDENCE

Why does drinking alcohol have such profound effects

on thought, mood, and behavior? And why does alcohol

dependence develop and persist in some people and not in

others? Scientists are addressing these questions and others

through neuroscience—the study of the brain, where both

alcohol intoxication and dependence begin. Through neuroscience research, scientists are gaining a better understanding

of how alcohol changes the brain and how those changes

in turn influence certain behaviors.

To function normally, the brain must maintain a careful

balance of chemicals called neurotransmitters—small molecules

involved in the brain’s communication system that ultimately

help regulate the body’s function and behavior. Just as a heavy

weight can tip a scale, alcohol intoxication can alter the delicate

balance among different types of neurotransmitter chemicals

and can lead to drowsiness, loss of coordination, and euphoria—

hallmarks of alcohol intoxication.

Remarkably, with ongoing exposure to alcohol, the brain

starts to adapt to these chemical changes. When alcohol is

present in the brain for long periods—as with long­term

heavy drinking—the brain seeks to compensate for its

effects. To restore a balanced state, the function of certain

neurotransmitters begins to change so that the brain can

perform more normally in the presence of alcohol. These

long­term chemical changes are believed to be responsible

for the harmful effects of alcohol, such as alcohol dependence.

Today, thanks to rapidly advancing technology, researchers

know more than ever about how alcohol affects the brain

and how the brain responds and adapts to these effects.

This Alcohol Alert summarizes some of what we know about

alcohol’s short­ and long­term effects on the brain and how

breakthroughs in neuroscience are leading to better treatments

for alcohol­related problems.

How Alcohol Changes the

Brain: Tolerance and

Withdrawal

As the brain adapts to alcohol’s presence over time, a heavy

drinker may begin to respond to alcohol differently than

someone who drinks only moderately. Some of these changes

may be behind alcohol’seffects, including

alcohol tolerance(i.e., having to drink

morein order to becomeintoxicated) (1)

and alcohol withdrawal symptoms.

These effects are associated with alcohol

dependence.

When the brain isexposed to alcohol, it

may become tolerant—or insensitive—

to alcohol’s effects. Thus, as a person

“ When alcohol is present in the brain

for long periods—as with long­term

heavy drinking—the brain seeks to

compensate for its effects.”
continues to drink heavily, he or she may need more

alcohol than before to become intoxicated. As tolerance

increases, drinking may escalate, putting a heavy drinker at

risk for a number of health problems—including alcohol

dependence.

Even as the brain becomes tolerant to alcohol, other changes

in the brain may increase some people’s sensitivity to alcohol.

Desire for alcohol may transition into a pathological craving

for these effects. This craving is strongly associated with

alcohol dependence (1).

Other changes in the brain increase a heavy drinker’s risk

forexperiencing alcohol withdrawal—a collection of symptoms

that can appear when a person with alcohol dependence

suddenly stops drinking. Withdrawal symptoms can be

severe, especially during the 48 hours immediately following a bout of drinking. Typical symptoms include profuse

sweating, racing heart rate, and feelings of restlessness and

anxiety (2). Research shows that alcohol­dependent people

may continue drinking to avoid experiencing withdrawal.

Feelings of anxiety associated with alcohol withdrawal can

persist long after the initial withdrawal symptoms have

ceased, and some researchers believe that—over the long

term—this anxiety is a driving force behind alcohol­use

relapse (3).

NEURONS AND SYNAPTIC TRANSMISSION

The brain transmits information through a

system of interconnected nerve cells known

as neurons. Signals travel rapidly along

chains of neurons using a combination of

electrical and chemical processes. These signals cause many of alcohol’seffects on behaviors,

such as tolerance, craving, and addiction.

Signals travel from one neuron to the next

through a process known as synaptic transmission. Synaptic transmission is made

possible by the neuron’s unique structure.

In addition to a main cell body, neurons

have two types of specialized thin branches:

axons and dendrites. Axons transmit messages

from one neuron to the next, and dendrites

receive those messages from nearby neurons.

Individual neurons are separated by tiny

gaps known as synapses.

Messages travel from one neuron to the next across synaptic gaps and bind to special docking molecules on

the receiving neuron’s dendrites. These docking molecules are known as neurotransmitter receptors. When a

neurotransmitter binds to a receptor, it changes the activity of the receiving neuron.

Depending on the situation, these changes might make the neuron either more likely or less likely to pass on, or

“fire,” the signal to the next neuron. If the signal is fired, it travels down the axon, sparking the release of more

neurotransmitters into the next synapse and passing the signal along to the dendrites of the next neuron. If a signal

is not fired, the signal stops.

SOURCE: Lovinger, D.M. Communication networks in the brain: Neurons, receptors, neurotransmitters, and alcohol. Alcohol Research & Health 31(3):196–214, 2008.

Synaptic Transmission Between Cells

2
 

The Brain’s Unique

Communication System

Tolerance and withdrawal are tangible evidence of alcohol’s

influence on the brain. Scientists now understand some of

the mechanisms that lead to these changes—changes that

begin with the brain’s unique communication system.
The brain communicates through a complex system of

electrical and chemical signals. These signals are vital to

brain function, sending messages throughout the brain,

which, in turn, regulate every aspect of the body’s function.

Neurotransmitter chemicals play a key role in this signal

transmission (4).

Under normal circumstances, the brain’s balance of neurotransmitters allows the body and brain to function unimpaired. Alcohol can cause changes that upset this balance,

impairing brain function. For example, the brain balances

the activity of inhibitory neurotransmitters, which work to

delay or stop nerve signals, with that of excitatory neurotransmitters, which work to speed up these signals. Alcohol

can slow signal transmission in the brain, contributing to

some of the effects associated with alcohol intoxication,

including sleepiness and sedation.

As the brain grows used to alcohol, it compensates for

alcohol’s slowing effects by increasing the activity of excitatory neurotransmitters, speeding up signal transmission.

In this way, the brain attempts to restore itself to a normal

state in the presence of alcohol. If the influence of alcohol

is suddenly removed (that is, if a long­term heavy drinker

stops drinking suddenly), the brain may have to readjust

once again: this may lead to the unpleasant feelings associated

with alcohol withdrawal, such as experiencing “the shakes”

or increased anxiety.

Neurotransmitters: A Key

to Effective Medications

for Alcoholism

As researchers learn more about how neurotransmitters

are involved in addiction, they can develop more effective

medications that target specific neurotransmitter systems.

Unfortunately, thereis no “magic bullet” for treating alcoholrelated problems. It is unclear why some people respond

well to certain medications, but others do not. However,exciting

new research is helping scientists learn more about how alcohol

affects different people. A handful of medications are now

availableto treat alcohol problems, many of which aim to alter

the short­ or long­term effects of alcohol by either interfering

with or imitating the actions of key neurotransmitters.

The table on page 4 provides information on some of the

drugs used to treat alcohol withdrawal and dependence as

well as brief descriptions of the neurotransmitter systems

the drugs target. Scientists still are seeking to understand

the details of how some of these medications work in the

brain, but studies suggest that, in some people, they can

be helpful in treating alcoholism and its consequences.

New Strategies for Studying

Alcohol and the Brain

Powerful imaging methods now allow researchers to study

how alcohol affects different brain systems and structures.

Some of these methods include positron emission tomography (PET), event­related potentials (ERPs), and magnetic

resonance imaging and magnetic resonance spectroscopy

(MRI/MRS). These methods are especially useful because

they allow researchers to see, in real time, how alcohol changes

the human brain. These imaging techniques—when used

with alcoholics, nonalcoholics, and children of alcoholics—

may help identify genetic risk factors for alcoholism (5).

PET is being used to track the changes that alcohol use

causes in specific neurotransmitter systems—changes that

may be the cause of alcohol’s short­term pleasurable effects

(i.e., intoxication) and long­term detrimental effects (i.e.,

alcohol dependence) (6). PET technology allows researchers

to see how these molecules behave. Forexample, researchers

are using PET to track the activity of dopamine, a neurotransmitter believed to contribute to alcoholism. With

this information, researchers can identify specific parts

of the dopamine system that could be targeted for the

development of medications to treat alcoholism (6).

Using ERP, researchers have identified markers that appear

in the brains of alcoholics and in children of alcoholics

(a population that is at high risk for developing alcoholism)

(7; for a review, see 8). A marker is a distinct characteristic

that can be associated with a certain group of people. Such

markers may be useful for identifying people who are at risk

for alcoholism. For example, scientists

have found that certain electrical currents

in the brain (as measured by a brainwave

“As researchers learn more about how

neurotransmitters are involved in

addiction, they can develop more

effective medications that target

specific neurotransmitter systems.”

3
 

called P300) are different in people

who are at risk for alcoholism. Research

shows that alcoholics have a blunted

P300 brainwave; that is, the peak of the

brainwave is much lower than in people

without an alcohol use disorder. Moreover,

this difference in P300 peak is evident in

children of alcoholics even before they

have taken their first drink. Certain

markers linked to alcoholism also are
Medications for Alcoholism
 

Food and DrugAdministration

Approved Medications

Treatment

Use

Target

Neurotransmitters

Effect

Benzodiazepines Treating alcohol

(Valium® and Xanax®) withdrawal

Disulfiram Preventing alcohol

(Antabuse®) consumption

Naltrexone Reducing/

(ReVia®

,Vivitrol®, stopping drinking

Naltrel®)

Acamprosate Enhancing abstinence

(Campral®)

GABA

(γ­aminobutyric acid)

Main effect on alcohol

metabolism rather than

in the brain

Opioids

Glutamate

Increases GABA activity, curbing

the brain’s “excitability” during its

withdrawal from alcohol, allowing the

brain to restore its natural balance.

Increases the concentration of

acetaldehyde, a toxic byproduct that

occurs when alcohol is broken down

(i.e.,metabolized) in the body. Excess

amounts of this byproduct cause

unpleasant symptoms, such as nausea

and flushing of the skin.

Blocks opioid receptors involved in

the pleasant sensations associated

with drinking.

Thought to dampen glutamate activity

and may reduce some of the hyperexcitability associated with alcohol

withdrawal.

Promising

Medications*

Original

Use

Target

Neurotransmitters

Potential

Use

Topiramate Treating seizures GABA and glutamate Appears effective in reducing drinking

(Topamax®) in alcohol­dependent patients.

Selective serotonin Treating depression Serotonin SSRIs have shown mixed results for

reuptake inhibitors and anxiety treating alcoholics with depression. May

(SSRIs) (fluoxetine reduce drinking in patients who developed

[Prozac®], sertraline alcohol dependence later in life.

[Zoloft®], and others)

Ondansetron Preventing nausea Serotonin May reduce drinking in patients who

(Zofran®

) and vomiting developed alcohol dependence early in life.

Baclofen (Kemstro®, Treating muscle GABA May have beneficial effects in encouraging

Lioresal®) spasms abstinence, especially in alcoholic

patients with liver cirrhosis.

Quetiapine Sometimes used in Dopamine and serotonin Early­stage trials indicate quetiapine

(Seroquel®) treating psychiatric might be effective in increasing rates of

disorders abstinence, and to be especially useful

in patients with severe alcoholism or in

those who developed alcohol dependence

early in life.

NOTE: *Not yet approved for use in the treatment of alcohol use disorders.

SOURCES: Lovinger, D.M. Communication networks in the brain: Neurons, receptors, neurotransmitters, and alcohol. Alcohol Research & Health 31(3):196–214, 2008.

Krishnan­Sarin, S.; O’Malley, S.; and Krystal, J.H. Treatment implications: Using neuroscience to guide the development of new pharmacotherapies for alcoholism. Alcohol Research

& Health 31(4):400–407, 2008.

4
 
found with other mental health disorders, including drug use

disorders, antisocial personality disorder, conduct disorder,

and attention deficit hyperactivity disorder (for a review, see

8), suggesting that there may be a genetic connection among

all of these disorders.

NewTechnology to Map

Alcohol’s Effects

With magnetic resonance imaging (MRI)/

magnetic resonance spectroscopy (MRS),

researchers use a powerful magnetic field to

generate a highly detailed “map” of the brain.

For example, one technique, known as functional

MRI (fMRI), allows researchers to “see” blood

flow to specific regions in the brain and, thus,

to identify which regions of the brain currently

are active. Using this technique, researchers are

exploring how alcohol affects brain function

and how brain function changes as alcohol

dependence develops over time (9).

In addition to imaging studies, researchers also are using

animals to study alcoholism. The results of these studies can

help researchers better understand how to treat alcoholism

in humans. In particular, animal models help scientists study

the genetic links involved in alcoholism. Researchers can

“turn off” genes that may be involved in alcohol addiction

in laboratory animals, giving them insight into how these

genes affect an animal’s behavior (10). For example, an animal

model could show whether an animal will still seek alcohol

once a specific gene has been turned off. Researchers also are

able to work with small clusters of cells from animal brains

and to study alcohol’s effects on a cellular level (11).

Animal studies allow researchers to explore how alcohol

damages the brain and how the brain begins to recover from

this damage with abstinence from drinking. Studies in rats

show that heavy episodic drinking (i.e., “binge drinking”)

can injure the brain by causing the death of neurons and

other components (12). These brain injuries may cause some

of the changes in thought and behavior that are associated

with alcohol dependence in humans (13). Animal studies

suggest that the brain can recover at least partially from this

damage. One method being investigated is the use of neural

stem cells, which, over time, may help to rewire new neurons

and repair damage to the brain’s communication system (14).

Conclusion

Neuroscience is showing that the pathways of addiction are

based in the brain. Using advanced techniques such as imaging methods and studies with animal models, researchers are

learning more about how alcohol interacts with the brain’s

communication system in different people.Innovativetechnology

also is helping identify the changes that occur in the brain’s

structure and function as a result of drinking, and how

alcohol disrupts the brain’s delicate chemical balance. This

information may help scientists understand why and how

alcoholism develops in different populations and ultimately

result in more effective and targeted therapies for alcohol

abuse and dependence.

References

(1) Gilpin, N.W., and Koob, G.F. Neurobiology of alcohol dependence: Focus on motivational mechanisms. Alcohol Research & Health 31(3):185–195, 2008. (2)

Majchrowicz, E. Induction of physical dependence upon ethanol and the associated

behavioral changes in rats. Psychopharmacologia 43(3):245–254, 1975. PMID:

1237914 (3) Koob, G.F. Alcoholism: Allostasis and beyond. Alcoholism: Clinical and

Experimental Research 27(2):232–243, 2003. PMID: 12605072 (4) Lovinger, D.M.

Communication networks in the brain: Neurons, receptors, neurotransmitters, and

alcohol. Alcohol Research & Health 31(3):196–214, 2008. (5) Hitzemann, R., and

Oberbeck, D. Strategies to study the neuroscience of alcoholism: Introduction. Alcohol

Research & Health 31(3):231–232, 2008. (6) Thanos, P.K.; Wang, G.J.; and Volkow,

N.D. Position emission tomography as a tool for studying alcohol abuse. Alcohol

Research & Health 31(3):233–237, 2008. (7) Begleiter, H.; Porjesz, B.; Bihari, B.; and

Kissin, B. Event­related brain potentials in boys at risk for alcoholism. Science

225:1493–1496, 1984. PMID: 6474187 (8) Porjesz, B.; Rangaswamy, M.; Kamarajan,

C.; et al. The utility of neurophysiological markers in the study of alcoholism. Clinical

Neurophysiology 116:993–1018, 2005. PMID: 15826840 (9) Nagel, B.J., and Kroenke,

C.D. The use of magnetic resonance spectroscopy and magnetic resonance imaging

in alcohol research. Alcohol Research & Health 31(3):243–246, 2008. (10) Adams,

C.A., and Zawada, W. M. On the use of short­interfering RNA to study alcohol­related

genes. Alcohol Research & Health 31(3):256–258, 2008. (11) Oberbeck, D. Laserassisted microdissection. Alcohol Research & Health 31(3):249–250, 2008. (12)

Crews, F.T., and Nixon, K. Mechanisms of neurodegeneration and regeneration in

alcoholism. Alcohol and Alcoholism 44(2):115–127, 2009 PMID: 18940959 (13)

Crews, F.T. Alcohol­related neurodegeneration and recovery: Mechanisms from animal models. Alcohol Research & Health 31(4):377–388, 2008. (14) Zhao, C.; Deng,

W.; and Gage, F.H. Mechanisms and functional implications of adult neurogenesis.

Cell 132(4):645–660, 2008. PMID: 18295581

5
 
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R e s o u r c e s

Source material for this AlcoholAlert originally appeared in Alcohol Research &
 

Health,Volume 31,Number 3,2008 and Alcohol Research & Health,Volume 31,
 

Number 4,2008.
 

Alcohol Research and Health 31(3):Neuroscience:Pathways toAlcohol Dependence

Part 1—Overview of the Neurobiology of Dependence. The first issue in this special

two­part series introduces what we know about alcohol’s effects on the brain, and

how these effects might lead to dependence. Articles explore the brain’s complex

communication systems, and how short­ and long­term alcohol use can affect these

systems. A special section highlights emerging technologies, such as brain imaging

and animal studies, which are helping researchers to understand even more about

alcohol’s effects on the brain.

Alcohol Research and Health 31(4): Neuroscience: Pathways to Alcohol Dependence

Part II—Neuroadaptation, Risk, and Recovery. The second issue in this series

describes how the brain’s own adaptations to the presence of alcohol may play a

key role in alcohol dependence, and how neuroscience is helping researchers target

medications to help people at risk for alcohol use disorders. Other articles show

how changes in the brain may lead to tolerance, withdrawal, and relapse to drinking.

For these and other resources, visit NIAAA’sWeb site, www.niaaa.nih.gov

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Full text of this publication is available on NIAAA’sWorldWideWeb site at www.niaaa.nih.gov.

All material contained in the Alcohol Alert is in the public domain and may be used or reproduced

without permission from NIAAA. Citation of the source is appreciated.
 

Copies of the Alcohol Alert are available free of charge from the National Institute on Alcohol Abuse and Alcoholism
 

Publications Distribution Center, P.O. Box 10686, Rockville, MD 20849–0686.