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 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 opiate–like 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 alcohol–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 cravings. 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.
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). 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 so–called “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 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 Target: 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.
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