National Institute on Alcohol Abuse and Alcoholism No. 61 April 2004 

Neuroscience Research and Therapeutic Targets 

Alcoholism, like other addictions, is a brain disorder. Research has shown that genes shape 

how an individual experiences alcohol—how intoxicating, pleasant, or sedating it is—and how 

susceptible he or she is to developing alcohol use disorders. Research has also shown that 

chronic heavy drinking causes long-term—and perhaps permanent—changes in the way the 

brain responds to alcohol. These parallel insights from neuroscience research are paving the 

way for new medications that will improve alcoholism treatment and relapse prevention. 

Addiction science has benefited from rapid progress in cellular and molecular research 

techniques, from the integration of scientific disciplines in the study of addiction-related 

behavior, and from the development of more appropriate animal models (1). Research in 

genetics is paying off in the identification of genes that influence the risk of developing alcoholism 

(2–7). Many of the genes being identified direct the production of proteins involved in the 

complex process of signaling between neurons in the brain. For example, genes that encode 

subunits of receptors for neurotransmitters such as GABA, serotonin, and others have been 

identified (see below for background on these neurotransmitters). Other genes related to 

alcoholism risk encode enzymes that metabolize alcohol. Gene discovery offers multiple 

benefits. Identification of risk-associated genes may provide a means of identifying people at 

risk. As important, knowing the genes and the proteins they encode is a key to understanding 

how alcohol interacts with this part of the cell’s machinery, how variants of the gene raise or 

lower risk, and how chronic exposure to alcohol can change gene expression (the translation 

of genes into proteins) and set the stage for addiction. Some of the genes being identified 

raise the risk of both alcoholism and so-called comorbid disorders, like depression, that often 

occur along with alcohol problems. Knowledge of these genes should provide insight into the 

brain mechanisms that underlie these disorders. Finally, identifying genes provides potential 

targets for medication development. A recent Alcohol Alert on the genetics of alcoholism 

describes some of the approaches being used to identify genes related to alcoholism risk (8). 

This Alcohol Alert provides a brief overview of what research is revealing about how alcohol 

affects the brain and how the resulting changes contribute to alcohol dependence. Also 

addressed is what research is showing about the effect of stressful life experiences on the 

brain and how they may contribute to risk of alcohol dependence and relapse to drinking. 

Beyond understanding how alcohol affects the brain, the hoped-for outcome of this work is 

the identification of neurologic targets for potential medications. Some of the medications in 

clinical use or testing that have come out of this work are reviewed below. 

Alcohol Interferes with Brain Cell Communication 

Large and often widespread networks of brain cells perform the brain’s essential functions: 

storing information, regulating basic body functions, and directing behavior. The basis of 

these brain networks is communication from cell to cell by chemical messengers called neurotransmitters. Released into narrow gaps, or synapses, between cells, neurotransmitters cross 

the synapse and activate proteins called receptors. Receptor activation, in turn, leads to a 

series of molecular interactions within the receiving cell. Some of the molecular interactions 

are short-term and remain localized to the area of the cell containing the receptors. Others 

Alcohol Alert, a publication of 

the National Institute on Alcohol 

Abuse and Alcoholism, provides 

timely information on alcohol 

research and treatment to 

health professionals and other 

interested people. This issue is 

the sixty-first in the series. 

Research in genetics 

is paying off in the 

identification of genes 

that influence the 

risk of developing 

alcoholism. 

A Commentary by NIAAA Director, Ting-Kai Li, M.D.. .............................................................5


U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service • National Institutes of Health 
result in lasting changes, at multiple locations throughout the cell, in protein expression, structure, and composition. 

Intoxication and other short-term (acute) effects of alcohol are caused largely by temporary, 

reversible changes in specific receptors and associated molecules. With repeated (chronic) 

alcohol exposure, long-lasting changes occur in receptors and in the series of chemical interactions they signal. However, neuroscientists have found that receptor changes are only one 

example of many permanent changes in the brain, collectively referred to as “neuroadaptation,” 

caused by the presence of alcohol. Strong evidence exists that neuroadaptation involves 

changes at many different levels, from the genetically directed production of critical proteins 

(9–12) to physical changes in the structure of the cells on both sides of the synapse—that is, 

both the signaling and the receiving cell. 

Unraveling these different aspects of neuroadaptation may be the key to understanding 

how addiction develops. Recent studies have linked neuroadaptation with tolerance (the need 

to drink more alcohol to achieve the same level of intoxication) (13,1) and with the symptoms 

of withdrawal (14). Neuroadaptation also appears to underlie the persistent sense of 

discomfort, often described as “craving,” that can lead to relapse even after long periods of 

abstinence (14–17). 

Medications from Neuroscience 

Based on neuroscience research, scientists are developing medications that potentially could 

target both the acute responses to alcohol and the neuroadaptations that can accompany 

chronic drinking. Potential medications may target specific receptor types, the series of 

chemical reactions set off by receptor activation, or the production of critical protein enzymes 

involved in these processes within cells. To use these strategies effectively and safely, however, researchers must first understand in detail where and how alcohol exerts its effects. 

Naltrexone and acamprosate are two medications that act on receptor systems in the brain 

on which alcohol is known to have an impact and that have shown some success for treating 

alcoholism. Naltrexone binds with receptors for endogenous opioids, naturally occurring opiatelike substances that stimulate pleasurable feelings and suppress pain. Animal studies 

suggest that opiate antagonists like naltrexone block some of alcohol’s rewarding effects. 

Clinical studies have reported that alcohol-dependent patients given naltrexone drink less 

frequently, and in smaller quantities, than patients given a placebo (18). Naltrexone has been 

approved by the U.S. Food and Drug Administration (FDA) for alcoholism treatment. 

Acamprosate’s precise mechanism of action is not yet known, but it is thought to affect 

activity of the neurotransmitter glutamate (18,19). In clinical studies in Europe, patients on 

acamprosate experienced higher abstinence rates, and for those who did relapse, longer 

periods of abstinence (18). Clinical studies using acamprosate are ongoing in the United 

States, but it has not yet been FDA approved. 

Despite promising results for some patients using naltrexone or acamprosate, not everyone 

responds. It is likely that different subtypes of alcoholics have different genetically determined 

traits shaping their response to alcohol and underlying their vulnerability to alcohol problems. 

For these reasons, the need remains for new medications, with a variety of drugs eventually 

providing a way to target treatment according to a person’s individual biology. 

Inhibitory and Excitatory Neurotransmitters: GABA and Glutamate 

One of the most powerful actions of alcohol is to reduce the overall level of brain activity by a 

combination of effects on two key neurotransmitters, GABA (gamma-aminobutyric acid) and 

glutamate. Alcohol enhances the activity of GABA, the brain’s chief inhibitory neurotransmitter. 

At the same time, alcohol reduces the excitatory effects of glutamate. These actions are the 

main reason that alcohol is often thought of as a depressant. 

GABA is the neurotransmitter-receptor system that has historically received the most 

attention in alcohol research, but it remains difficult to exploit therapeutically. Its major receptor 

type, the GABA-A receptor, is involved in many of alcohol’s acute and chronic effects (20–25). 

Medications that block GABA’s ability to bind at the GABA-A receptor also block some of 

alcohol’s effects (1), but because this receptor system plays a role in so many vital brain functions, blocking it has side effects. Current GABA-A–blocking drugs can cause convulsions, a 

side effect that must be eliminated before this receptor system can be targeted for therapy. 

Baclofen, a drug that activates another type of GABA receptor (GABA-B), has recently 

been shown in a preliminary study to be effective in inducing abstinence from alcohol and 

reducing alcohol craving and consumption in alcoholics (26). Use of baclofen to treat alcoholUnraveling these 

different aspects of 

neuroadaptation may 

be the key to 

understanding how 

addiction develops. 

Naltrexone and 

acamprosate are two 

medications that act on 

receptor systems in the 

brain on which alcohol 

is known to have an 

impact and that have 

shown some success 

for treating alcoholism. 

Alcohol enhances the 

activity of GABA, the 

brain’s chief inhibitory 

neurotransmitter. At 

the same time, alcohol 

reduces the excitatory 

effects of glutamate. 

2 
dependent patients merits further investigation. Treatment for withdrawal commonly involves 

drugs that act on GABA-A receptors. Investigators are searching for new, safer drugs that 

increase GABA activity. One such drug—gabapentin—is currently being tested (27). 

Alcohol reduces the activity of the neurotransmitter glutamate by interacting with NMDA 

receptors, one of several classes of receptor to which glutamate binds. Preclinical data suggest 

that reducing NMDA neurotransmission may be effective in treating alcoholism. Memantine, 

a drug that reduces NMDA receptor function, looks promising as an anticraving drug and in 

treating alcohol dependence. Clinical trials to establish its efficacy are being contemplated 

(28). More recently, it has been shown that the anticonvulsant drug, topiramate, which acts 

on another class of glutamate receptors (AMPA-kainate receptors), decreases glutamate 

activity while increasing GABA activity. A recent study reported that alcohol-dependent 

patients on topiramate had fewer drinking days and had fewer drinks on days they did drink 

(compared with participants taking a placebo) (29). Topiramate reportedly reduced craving. 

Additional studies are needed to confirm this work and provide information on how best 

to use topiramate: on which groups of patients, in what dosage, and with what types of 

psychosocial therapy. 

Receptors Signaling Pleasure: Serotonin and Cannabinoids 

Other candidates for drug treatment are aimed at brain receptors thought to be involved with 

the mood-elevating, rewarding sensations associated with alcohol. The neurotransmitter 

serotonin is involved in the regulation of attention, emotion, and motivation. Alcohol alters 

serotonin neurotransmission (30). In addition, depression is a common co-occurring disorder 

with alcoholism. One class of drugs used to treat depression—selective serotonin reuptake 

inhibitors (SSRIs)—increases the availability of serotonin in the synapse. Studies examining 

whether SSRIs such as fluoxetine (Prozac) and sertraline (Zoloft) might be helpful in treating 

alcoholism co-occurring with depression have produced mixed results (31–33). What these 

studies suggest is that individuals vary not only in terms of their risk of alcohol problems, but 

in how they respond to both pharmacologic and behavioral treatment. 

Research on other drugs that affect serotonin neurotransmission also points to variability in 

individual responses to treatment. For example, the drug ondansetron reduces the activity of 

a serotonin receptor (5-HT3) on which alcohol is known to act and has been shown to reduce 

the desire to drink in humans. A clinical trial demonstrated that ondansetron was most effective in reducing the frequency and quantity of drinking in early-onset (alcohol-dependent 

before age 25) vs. late onset (alcohol-dependent after age 25) alcoholics (34). Larger scale 

studies are needed to confirm these results. Continued research on genetics and 

neurophysiology should help refine the understanding of what shapes individual responses to 

drugs and how treatments can be tailored accordingly (35). 

Another recent candidate as a target for therapy is a brain receptor (CB1) that responds to 

endocannabinoids, innate substances that interact with the CB1 receptor in a manner similar 

to the active ingredients in marijuana. Like serotonin, the endocannabinoid system is involved 

in the rewarding effects of alcohol (36–40,12,41). A drug that blocks CB1 has been found to 

reduce alcohol consumption in rats (42–44), suggesting the possibility of using such medications to help people undergoing alcohol detoxification (45). 

Cellular Enzymes 

Another strategy for developing therapies focuses not on receptors but on enzymes within the 

cell that are involved in the brain’s neuroadaptation to alcohol. Chronic drinking alters the 

distribution of these enzymes within cells and can change the way brain cells respond to 

alcohol (46–48,12). An enzyme called protein kinase C (PKC) is the subject of much research 

because it helps shape the level of sensitivity to alcohol’s behavioral effects, at least in part 

through its interaction with the GABA-A receptor. In a study looking at PKC and alcohol 

sensitivity, mutant mice that lacked a form of PKC (PKC epsilon) were more sensitive than 

their littermates to the behavioral effects of alcohol. Without alcohol, the mutant mice did not 

appear sleepy or sedated, however (46). More recently, the same team reported that the 

mice lacking PKC epsilon do not work as hard for alcohol (by pressing a lever) as their littermates and do not show the same increases in dopamine that are usually associated with the 

reinforcing effects of alcohol. Withdrawal-associated seizures are also less severe in these 

mutated mice (49,50). This suggests that medications developed to inhibit PKC epsilon might 

reduce alcohol reward as well as help treat seizures, but without the sedating effects of other 

drugs that act on GABA neurotransmission. 

Other candidates for 

drug treatment are 

aimed at brain receptors 

thought to be involved 

with the mood-elevating, 

rewarding sensations 

associated with alcohol. 

The drug ondansetron 

reduces the activity of a 

serotonin receptor 

(5-HT3) on which 

alcohol is known to act 

and has been shown 

to reduce the desire 

to drink. 

An enzyme called 

protein kinase C (PKC) 

is the subject of much 

research because it 

helps shape the level of 

sensitivity to alcohol’s 

behavioral effects, at 

least in part through 

its interaction with the 

GABA-A receptor. 

3 
Scanning the Genome 

Using gene markers (known variations in genetic material spaced along the DNA chains that 

make up chromosomes) scientists can scan the entire genome for chromosomal stretches 

that are associated with alcoholism risk. NIAAA’s Collaborative Study on the Genetics of 

Alcoholism (COGA) has identified stretches on chromosomes 1, 2, 4, 7, 15, and 16 that are 

associated with alcoholism risk (51–54). Work by other investigators has also found confirming 

evidence for linkage to chromosome 1 (55), and in American Indians, to chromosomes 1 and 

4 (56,57). Recently COGA investigators found evidence that variations in a gene on chromosome 4 encoding the alpha subunit of the GABA-A receptor and, on chromosome 15, in the 

GABA-A receptor gene GABRG3 influence alcoholism risk (5,4). These findings bring the 

work full circle, tying risk associated with a chromosomal location to a specific gene known to 

be involved in the response to alcohol. 

Other emerging methods can be used to assess the activities of thousands of genes at 

once. This new technology (microarray gene analysis) promises to expand the pool of target 

molecules for alcoholism researchers and to help them zero in on the brain areas most 

affected by the disorder. It is possible to compare the patterns of protein production in the 

brain cells of animals bred to respond differently to alcohol or with different exposure to 

alcohol; or, of people with and without alcohol addiction (in this case, cells are obtained at 

autopsy). Comparisons of which genes are active in different brain areas can direct attention 

to the regions where alcohol exerts its greatest effects and to genes involved in the alcohol 

response (9,58–61,12,11). A recent paper reported on the identification of a gene that is 

differentially expressed in brain regions of inbred alcohol-preferring and nonpreferring rats 

(62). The gene codes for alpha synuclein, a protein that has been shown to be involved in 

neurotransmission. Another recent study looked specifically at changes in gene expression in 

mice shortly after a dose of alcohol. Out of about 24,000 genes, the screen identified 61 

responding in a significant way to alcohol, including sets of genes that have roles such as 

protecting cells from injury and glucose metabolism, as well as being involved with behavioral 

responses to alcohol (63). Further research will clarify the roles of all these genes in the 

body’s response to alcohol. 

Neurosystems—The Circuits and Networks of Stress 

Neuroscience research is beginning to reveal how different brain regions contribute to the 

complex process of addiction (64). The brain is subdivided into many specialized regions, 

which set up connections, or “circuits,” with other regions. These circuits, in turn, interact with 

other circuits to form networks that integrate the functions of the brain. 

The pleasurable effects of drugs of addiction, including alcohol, are mediated by the socalled “reward” circuits of the brain (65,16,1). Following short-term exposure to alcohol, these 

circuits are able to return to their normal level of function. With repeated exposure to alcohol, 

however, the responsiveness of these circuits changes. For example, studies have demonstrated in rats that the function of neurotransmitters involved in reward is reduced during withdrawal from alcohol, while at the same time, stress-related systems are activated (1). Levels 

of dopamine, a neurotransmitter associated with reward, are lower in rats following withdrawal 

than before the rats were made dependent. The rats also react with increased anxiety to 

stressful situations following withdrawal. Research suggests that the discomfort and distress 

that result from these persistent changes in brain reward and stress circuits underlie the 

compelling motivation to drink by alcohol-dependent individuals. 

The link between alcohol consumption and stress is complex. Studies suggest that exposure to stress may lead to the initiation and continued use of alcohol (17,66). In fact, many 

researchers believe that alcohol’s stress-relieving effect is what prompts most people to drink 

(67). While alcohol use may temporarily relieve the symptoms of stress, chronic drinking not 

only can lead to alcohol-related problems, it may exacerbate the adverse effects of stress, 

leaving the brain in a state of permanent “physiological stress.” This effect may help explain 

why alcoholics are likely to relapse during stressful life events, even after months or years of 

abstinence (16,1). 

Among the molecules involved in regulating physiological reactions to stress, two in particular 

have drawn the attention of alcohol researchers. Corticotropin-releasing factor (CRF) is a critical 

messenger in the stress circuits that work primarily within the brain; neuropeptide Y (NPY) is 

involved with processes ranging from appetite to memory and stress responses (68–73). In a 

recent study, both alcohol and CRF increased GABA neurotransmission in mice—except in 

Comparisons of which 

genes are active in 

different brain areas 

can direct attention to 

the regions where 

alcohol exerts its 

greatest effects and to 

genes involved in the 

alcohol response. 

The pleasurable effects 

of drugs of addiction, 

including alcohol, 

are mediated by the 

so-called “reward” 

circuits of the brain. 

While alcohol use may 

temporarily relieve the 

symptoms of stress, 

chronic drinking not 

only can lead to alcoholrelated problems, it may 

exacerbate the adverse 

effects of stress, leaving 

the brain in a state 

of permanent “physiological stress.” 

4 
mice missing one of two types of CRF receptors (74). This suggests that the missing receptors 

(CRF1) are a key link between the GABA-enhancing (and rewarding) effects of alcohol and the 

neurobiology of stress. 

Among NPY’s actions, it appears to counteract CRF effects. Research has linked chronic 

alcohol intake to imbalances in CRF and NPY (68). Both these molecules are logical targets 

for therapeutic research. 

Through basic neuroscience research, scientists are gaining a better understanding of how 

neuroadaptation sets the stage for alcohol addiction, and how stress can influence both 

dependence and relapse. Development of effective new medications for alcoholism requires 

a strategy that takes into account the many different possible interactions of alcohol with the 

brain, and the genetically determined variability among individuals. 

Neuroscience Research and Therapeutic Targets—A Commentary by 

NIAAA Director Ting-Kai Li, M.D. 

Alcohol interacts with the brain in complex ways. Its short-term effects can transiently alter 

behavior, while long-term exposure to alcohol can result in lasting changes in the brain, or 

neuroadaptation. Each point in the course of alcohol’s interactions with cell surface receptors, 

intracellular messenger molecules, genes, and brain circuits offers a potential target for 

pharmacologic intervention. The promise of interdisciplinary research in neuroscience is to link 

genetic, molecular, cellular, anatomic, and behavioral data and provide both an understanding 

of how individuals respond to alcohol and a guide for targeting prevention and treatment. 

References 

(1) Koob, G.F. Alcoholism: Allostasis and beyond. Alcoholism: Clinical and Experimental Research 27(2):232–243, 2003. (2) Wernicke, C.; Samochowiec, 

J.; Schmidt, L.G.; et al. Polymorphisms in the N-methyl-D-aspartate receptor 1 and 2B subunits are associated with alcoholism-related traits. Biological 

Psychiatry 54:922–928, 2003. (3) Miyatake, R.; Furukawa, A.; Matsushita, S.; et al. Functional polymorphisms in the Sigma1 receptor gene associated with 

alcoholism. Biological Psychiatry 55:85–90, 2004. (4) Dick, D.M.; Edenberg, H.J.; Xuei, X.; et al. Association of GABRG3 with alcohol dependence. 

Alcoholism: Clinical and Experimental Research 28(1):4–9, 2004. (5) Edenberg, H.; Dick, D.M.; Xuei, X.; et al. Variations in GABRA2, encoding the alpha2 

subunit of the GABAA, are associated with alcohol dependence and with brain oscillations. American Journal of Human Genetics 74:705–714, 2004. (6) 

Herman, A.I.; Philbeck, J.W.; Vasilopoulos, N.L.; and Depetrillo, P.B. Serotonin transporter promoter polymorphism and differences in alcohol consumption 

behaviour in a college student population. Alcohol and Alcoholism 38:446–449, 2003. (7) Ozaki, N.: Goldman: Kaye, W.H.; et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Molecular Psychiatry 8:933–936, 2003. (8) National Institute on Alcohol Abuse 

and Alcoholism (NIAAA). The genetics of alcoholism. Alcohol Alert No. 60. Rockville, MD: NIAAA, 2003. (9) Lewohl, J.M.; Wang, L.; Miles, M.F.; et al. 

Gene expression in human alcoholism: Microarray analysis of frontal cortex. Alcoholism: Clinical and Experimental Research 24(12):1873–1882, 2000. (10) 

Heinz, A., and Mann, K. Neurodegeneration and neuroadaptation in alcoholism. In: Agarwal, D.P., and Seitz, H.K., eds. Alcohol in Health and Disease. New 

York: Marcel Dekker, 2001. pp. 225–241. (11) Crabbe, J.C. Genetic contributions to addiction. Annual Review of Psychology 53:435–462, 2002. (12) 

Hoffman, P.L.; Miles, M.; Edenberg, H.J.; et al. Gene expression in brain: A window on ethanol dependence, neuroadaptation, and preference. Alcoholism: 

Clinical and Experimental Research 27(2):155–168, 2003. (13) Kiianmaa, K.; Hyytiä, P.; Samson, H.H.; et al. New neuronal networks involved in ethanol 

reinforcement. Alcoholism: Clinical and Experimental Research 27(2):209–219, 2003. (14) Hoffman, P.L.; Morrow, L.; Phillips, T.J.; and Siggins, G.R. 

Neuroadaptation to ethanol at the molecular and cellular levels. In: Noronha, A.; Eckardt, M.; and Warren, K., eds. Review of NIAAA’s Neuroscience and 

Behavioral Research Portfolio. NIAAA Research Monograph No. 34. NIH Pub. No. 00–4579. Bethesda, MD: National Institute on Alcohol Abuse and 

Alcoholism, 2000. pp. 85–188. (15) Weiss, F. Neuroadaptive changes in neurotransmitter systems mediating ethanol-induced behaviors. In: Noronha, A.; 

Eckardt, M.; and Warren, K., eds. Review of NIAAA’s Neuroscience and Behavioral Research Portfolio. NIAAA Research Monograph No. 34. NIH Pub. No. 

00–4579. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism, 2000. pp. 261–313. (16) Koob, G.F., and Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24(2):97–129, 2001. (17) Kreek, M.J.; LaForge, K.S.; and Butelman, E. Pharmacotherapy of 

addictions. Nature Reviews Drug Discovery 1:710–726, 2002. (18) National Institute on Alcohol Abuse and Alcoholism (NIAAA). Tenth Special Report 

to the U.S. Congress on Alcohol and Health. NIH Pub. No. 00–1583. Bethesda, MD: NIAAA, 2000. (19) Johnson, B.A., and Ait-Daoud, N. Medications to 

treat alcoholism. Alcohol Research & Health 23(2):99–106, 1999. (20) Mehta, A.K., and Ticku, M.K. An update on GABAA receptors. Brain Research 

Reviews 29(2–3):196–217, 1999. (21) Buck, K.J., and Finn, D.A. Genetic factors in addiction: QTL mapping and candidate gene studies implicate 

GABAergic genes in alcohol and barbiturate withdrawal in mice. Addiction 96(1):139–149, 2000. (22) Loh, E.W., and Ball, D. Role of the GABAAβ2, 

GABAAα6, GABAAα1, and GABAAγ2 receptor subunit genes cluster in drug responses and the development of alcohol dependence. Neurochemistry 

International 37(5–6):413–423, 2000. (23) Cagetti, E.; Liang, J.; Spigelman, I.; and Olson, R.W. Withdrawal from chronic intermittent ethanol treatment 

changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. 

Molecular Pharmacology 63(1):53–64, 2003. (24) Blednov, Y.A.; Jung, S.; Alva, H.; et al. Deletion of the α1 or β2 subunit of GABAA receptors reduces 

actions of alcohol and other drugs. Journal of Pharmacology and Experimental Therapeutics 304(1):30–36, 2003. (25) Kralic, J.E.; Wheeler, M.; Renzi, K.; et 

al. Deletion of GABAA receptor α1 subunit-containing receptors alters responses to ethanol and other anesthetics. Journal of Pharmacology and Experimental 

Therapeutics 305(2):600–607, 2003. (26) Addolorato, G.; Caputo, F.; Capiristo, E.; et al. Baclofen efficacy in reducing alcohol craving and intake: A preliminary double-blind randomized controlled study. Alcohol and Alcoholism 37(5):504–508, 2002. (27) Bonnet, U.; Banger, M.; Leweke, M.; et al. Treatment of 

acute alcohol withdrawal with gabapentin: Results from a controlled two-center trial. Journal of Clinical Psychopharmacology 23(5):514–519, 2003. (28) 

Bisaga, A., and Evans, S.M. Acute effects of memantine in combination with alcohol in moderate drinkers. Psychoparmacology 172:16–24, 2004. (29) 

Johnson, B.A.; Ait-Daoud, N.; Bowden, C.L.; et al. Oral topiramate for treatment of alcohol dependence: A randomized controlled trial. Lancet 

361(9370):1677–1685, 2003. (30) Lovinger, D.M. Serotonin’s role in alcohol’s effects on the brain. Alcohol Health & Research World 21(2):114–120, 1997. 

(31) Cornelius, J.R.; Salloum, I.M.; Ehler, J.G.; et al. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Archives of General Psychiatry 

54(8):700–705, 1997. (32) Moak, D.H.; Anton, R.F.; Latham, P.K.; et al. Sertraline and cognitive behavioral therapy for depressed alcoholics: Results of a 

placebo-controlled trial. Journal of Clinical Psychopharmacology 23(6):553–562, 2003. (33) Pettinati, H.M.; Volpicelli, J.R.; Luck, G.; et al. Double-blind clinical trial of sertraline treatment for alcohol dependence. Journal of Clinical Psychopharmacology 21(2)143–153, 2001. (34) Johnson, B.A.; Roache, J.D.; 

Javors, M.A.; et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients. Journal of the American Medical Association 

284(8):963–971, 2000. (35) Kranzler, H.R. Medications for alcohol dependence. Journal of the American Medical Association 284:1016–1017, 2000. (36) 

Childers, S.R., and Breivogel, C.S. Cannabis and endogenous cannabinoid systems. Drug and Alcohol Dependence 51(1–2):173–187, 1998. (37) 

Basavarajappa, B.S., and Hungund, B.L. Neuromodulatory role of the endocannabinoid signaling system in alcoholism: An overview. Prostaglandins, 

Leukotrienes and Essential Fatty Acids 66(2–3):287–299, 2002. (38) Hungund, B.L.; Basavarajappa, B.S.; Vadasz, C.; et al. Ethanol, endocannabinoids, 

and the cannabinoidergic signaling system. Alcoholism: Clinical and Experimental Research 26(4):565–574, 2002. (39) González, S.; Cascio, M.G.; 

5 
Fernándo-Ruiz, J.; et al. Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol, or cocaine. Brain Research 954:73–81, 

2002. (40) Schmidt, L.G.; Samochowiec, J.; Finckh, U.; et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug and Alcohol Dependence 65(3):221–224, 2002. (41) Wang, L.; Liu, J.; Harvey-White, J.; et al. Endocannabinoid signaling via cannabinoid receptor 1 

is involved in ethanol preference and its age-dependent decline in mice. Proceedings of the National Academy of Sciences U.S.A. 100(3):1393–1398, 2003. (42) 

Hungund, B.L., and Basavarajappa, B.S. Role of brain’s own marijuana, anandamide and its cannabinoid receptors (CB1) in alcoholism. Recent Research 

Developments in Neurochemistry 3(Part 1):9–26, 2000. (43) Freedland, C.S.; Sharpe, A.L.; Samson, H.H.; and Porrino, L.J. Effects of SR141716A on ethanol and 

sucrose self-administration. Alcoholism: Clinical and Experimental Research 25(2):277–282, 2001. (44) Vacca, G.; Serra, S.; Brunetti, G.; et al. Boosting effect of 

morphine on alcohol drinking is suppressed not only by naloxone but also by the cannabinoid receptor antagonist, SR 141716. European Journal of Pharmacology 

445(1–2):55–59, 2002. (45) Lallemand, F.; Soubrié, P.H.; and De Witte, P.H. Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic 

ethanol administration. Alcoholism: Clinical and Experimental Research 25(9):1317–1323, 2001. (46) Hodge, C.W.; Mehmert, K.K.; Kelley, S.P.; et al. 

Supersensitivity to allosteris GABAA receptor modulators and alcohol in mice lacking PKCε. Nature Neuroscience 2(11):997–1002, 1999. (47) Nuwayhid, S.J., 

and Werling, L.L. σ1receptor agonist-mediated regulation of N-methyl-D-aspartate-stimulated [3H]dopamine release is dependent upon protein kinase C. Journal of 

Pharmacology and Experimental Therapeutics 304(1):364–369, 2003. (48) Proctor, W.R.; Poelchen, W.; Bowers, B.J.; et al. Ethanol differentially enhances hippocampal GABAA receptor-mediated responses in protein kinase Cγ (PKCγ) and PKCε null mice. Journal of Pharmacology and Experimental Therapeutics 

305(1):264–270, 2003. (49) Olive, M.F.; Mehmert, K.K.; Messing, R.O.; and Hodge, C.W. Reduced operant ethanol self-administration and in vivo mesolimbic 

dopamine responses to ethanol in PKCε-deficient mice. European Journal of Neuroscience 12:4131–4140, 2000. (50) Olive, M.F.; Mehmert, K.K.; Nannini, A.; et 

al. Reduced ethanol withdrawal severity and altered withdrawal-induced c-fos expression in various brain regions of mice lacking protein kinase C-epsilon. 

Neuroscience 103:171–179, 2001. (51) Foroud, T.; Bucholz, K.K.; Edenberg, H.J.; et al. Linkage of an alcoholism-related severity phenotype to chromosome 16. 

Alcoholism: Clinical and Experimental Research 22(9):2035–2042, 1998. (52) Foroud, T.; Edenberg, H.J.; Goate, A.; et al. Alcoholism susceptibility loci: 

Confirmation studies in a replicate sample and further mapping. Alcoholism: Clinical and Experimental Research 24(7):933–945, 2000. (53) Reich, T.; Edenberg, 

H.J.; Goate, A.; et al. A genome-wide search for genes affecting the risk for alcohol dependence. American Journal of Medical Genetics (Neuropsychiatric 

Genetics) 81:207–215, 1998. (54) Song, J.; Koller, D.L.; Foroud, T.; et al. Association of GABAA receptors and alcohol dependence and the effects of genetic 

imprinting. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 117B:39–45, 2003. (55) Lappalainen, J.; Kranzler, H.R.; Petrakis, I.; et al. 

Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus. Molecular Psychiatry 9:312–319, 2004. (56) Ehlers, C.L.; Gilder, D.A.; Wall, 

T.L.; et al. Genomic screen for loci associated with alcohol dependence in Mission Indians. American Journal of Medical Genetics Part B (Neuropsychiatric 

Genetics). Early View, published online (www3.interscience.wiley.com), June 7, 2004. (57) Long, J.C.; Knowler, W.C.; Hanson, R.L.; et al. Evidence for genetic 

linkage to alcohol dependence on chromosome 4 and 11 from an autosome-wide scan in an American Indian population. American Journal of Medical Genetics 

(Neuropsychiatric Genetics) 81:216–221, 1998. (58) Thibault, C.; Lai, C.; Wilke, N.; et al. Expression profiling of neural cells reveals specific patterns of ethanolresponsive gene expression. Molecular Pharmacology 58(6):1593–1600, 2000. (59) Mayfield, R.D.; Lewohl, J.M.; Dodd, P.R.; et al. Patterns of gene expression 

are altered in the frontal and motor cortices of human alcoholics. Journal of Neurochemistry 81(4):802–813, 2002. (60) Rimondini, R.; Arlinde, C.; Sommer, W.; 

and Heilig, M. Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol. FASEB 

Journal 16(1):27–35, 2002. (61) Saito, M.; Smiley, J.; Toth, R.; and Vadasz, C. Microarray analysis of gene expression in rat hippocampus after chronic ethanol 

treatment. Neurochemical Research 27(10):1221–1229, 2002. (62) Liang, T.; Spence, J.; Liu, L.; et al. Alpha-synuclein maps to a quantitative trait locus for alcohol 

preference and is differentially expressed in alcohol-preferring and nonpreferring rats. Proceedings of the National Academy of Sciences of the U.S.A. 

100(8):4690–4695, 2003. (63) Treadwell, J.A., and Singh, S.M. Microarray analysis of mouse brain gene expression following acute ethanol treatment. 

Neurochemical Research 29:357–369, 2004. (64) Roberts, A.J., and Koob, G.F. The neurobiology of addiction. Alcohol Health & Research World 21(2):101–106, 

1997. (65) Hernandez-Avila, C.A.; Oncken, C.; Van Kirk, J.; et al. Adrenocorticotropin and cortisol responses to a naloxone challenge and risk of alcoholism. 

Biological Psychiatry 51(8):652–658, 2002. (66) Kreek, M.J., and Koob, G.F. Drug dependence: Stress and dysregulation of brain reward pathways. Drug and 

Dependence 51:23–47, 1998. (67) Sayette, M.A. An appraisal-disruption model of alcohol’s effects on stress responses in social drinkers. Psychological Bulletin 

114:459–476, 1993. (68) Slawecki, C.J.; Somes, C.; and Ehlers, C.L. Effects of chronic ethanol exposure on neurophysiological responses to corticotropin-releasing 

factor and neuropeptide Y. Alcohol and Alcoholism 34(3):289–299, 1999. (69) Thiele, T.E.; Miura, G.I.; Marsh, D.J.; et al. Neurobiological responses to ethanol in 

mutant mice lacking neuropeptide Y or the Y5 receptor. Pharmacology, Biochemistry and Behavior 67(4):683–691, 2000. (70) Caberlotto, L.; Thorsell, A.; 

Rimondini, R.; et al. Differential expression of NPY and its receptors in alcohol-preferring AA and alcohol-avoiding ANA rats. Alcoholism: Clinical and Experimental 

Research 25(11):1564–1569, 2001. (71) Lappalainen, J.; Kranzler, H.R.; Malison, R.; et al. A functional neuropeptide Y Leu7Pro polymorphism associated with 

alcohol dependence in a large population sample from the United States. Archives of General Psychiatry 59(9):825–831, 2002. (72) Thorsell, A.; Rimondini, R.; 

and Heilig, M. Blockade of central neuropeptide Y (NPY) Y2 receptors reduces ethanol self-administration in rats. Neuroscience Letters 332(1):1–4, 2002. (73) 

Pandey, S.C.; Carr, L.G.; Heilig, M.; et al. Neuropeptide Y and alcoholism: Genetic, molecular, and pharmacological evidence. Alcoholism: Clinical and 

Experimental Research 27(2):149–154, 2003. (74) Nie, Z.; Schweitzer, P.; Roberts, A.J.; et al. Ethanol augments GABAergic transmission in the central amygdale 

via CRF1 receptors. Science 303:1512–1514, 2004. 

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