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The Effects of Alcohol on the Brain

Scientists used to think of alcohol as a membrane disruptor with a generalized effect all over the brain, as the small molecule can freely diffuse across the blood–brain barrier. They now know that there are particular cells in the brain that alcohol targets by binding certain hydrophobic pockets on their surface receptors. The gamma-aminobutyric acid (GABA) receptor is one of these. "Alcohol is an indirect GABA agonist," says Koob.

GABA is the major inhibitory neurotransmitter in the brain, and GABA-like drugs are used to suppress spasms. Alcohol is believed to mimic GABA's effect in the brain, binding to GABA receptors and inhibiting neuronal signaling.

Alcohol also inhibits the major excitatory neurotransmitter, glutamate, particularly at the N-methyl-d-aspartate (NMDA) glutamate receptor. And it releases other inhibitors, such as dopamine and serotonin. Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called "reward centers." However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement. In fact, multiple neurotransmitters in various parts of the brain combine to make the consumption of small doses of alcohol enjoyable.

"Alcohol tends to activate the whole reward system," says Koob, who is particularly interested in the effects of alcohol in the amygdala.

The neurochemical effects of alcohol cause a range of short-term effects—from a mild buzz to slow reaction times, which make drunk driving so dangerous. In the long term, these effects are also the basis for two of the defining characteristics of addiction: tolerance and dependence.

Tolerance and Overdrinking

Tolerance to alcohol is one aspect of alcoholism that leads to overdrinking. Tolerance can be acute, in one bout of drinking, or long-term, requiring an ever-larger dose to get the same effect over time.

The effect of acute tolerance is a common experience for anyone who has had more than a few drinks. Initially, the first drink has a relaxing effect, but as a person continues drinking, it takes more and more alcohol to produce the same effect. Some people have more acute tolerance than others—probably due to genetic factors. "These are the people who can drink anybody else under the table," says Koob. He adds that these people may also be at increased risk of developing dependence on alcohol because of their increased tolerance.

Dependence to alcohol is linked to the interaction of alcohol with the brain's stress system, which alcohol activates. The major component of the brain stress system is the corticotropin-releasing factor (CRF) in the amygdala and related areas, which activates sympathetic and behavioral responses to stress. A normal stress response sees CRF recruiting other parts of the brain to help adapt the mind and body to deal with the physical and mental "stressors" that challenge it. Alcohol interacts in such a way as to acutely reduce CRF levels in the brain; chronic alcoholism does the opposite.

Koob hypothesizes that there also may be individuals who are at increased risk of becoming alcoholics because their genetic makeup causes them to have higher CRF levels than normal.

"They may be drinking to feel normal—they may drink to tame a hyperactive CRF stress system in the brain," he says.

Unfortunately, CRF and the stress system adjust to the alcohol. CRF is hypothesized to persist at artificially high levels in the brain while reward neurotransmitters are compromised. In alcoholism, the effect is even more pronounced and results in an equilibration of neurotransmitter levels at artificial, "allostatic" set-points—an equilibration driven by chronic alcohol ingestion. In the absence of alcohol, the alcoholic feels ill because his or her body cannot easily reverse these artificial levels (for example, high CRF and low reward neurotransmission).

This ill feeling may contribute to the tendency of the alcoholic to overdrink—a danger because of the toxic effect on the brain and body of subjecting oneself to so much alcohol.

Sadly, the brain often does not perceive the consequences of the short-term relief that the alcohol brings. When a person overdrinks, there is depleted GABA function in the brain and also, possibly, a hyper-excitable glutamate system. Alcoholics feel good while they are boozing. However, this short-term relief makes the whole system worse off.

Understanding Stress is Important for Treatment

Not only is stress part of the spiral disregulation of motivational processes involved in the development of alcoholism, but stress is one of the most common states associated with relapse. Relapse also occurs as a consequence of behavioral patterns, such as walking by the old saloon or hanging around with familiar drinking buddies. "Before you know it, you're back into it," says Koob.

Alcoholics drink when they're happy, alcoholics drink when they're sad, and they drink when they are stressed. "Any excuse to drink," he says.

In the treatment of alcoholism, a person is especially vulnerable to relapse for a year to 18 months after cessation of drinking, a period Koob refers to as "protracted abstinence." One of Koob's research interests is in protracted abstinence and the residual changes in the brain that take place during it.

These are very important studies because behavior plays such a large role in relapse, and behavioral therapy is a prominent part of the recovery process. Most alcoholism treatment programs involve some form of behavioral therapy—whether through professional counseling or a group like Alcoholics Anonymous. The goal of much of Koob's work is to someday help individuals who have become addicted to alcohol.

"It's very possible that we are going to find brain areas that code for certain proteins responsible for the individual differences that make 15 percent of the population vulnerable to alcoholism and/or that protect 85 percent," says Koob.

"Once we know the circuits and the basis for alcoholism, we can develop new targeted treatments."



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Effects of drugs of abuse on subregions of the extended amygdala. Click to enlarge












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