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Research Reveals More About Alcoholism’s Complex Action on Brain

A report on the effects of alcohol on brain synapses is challenging a widely held theory of alcoholism’s mechanism of action. The findings could lead to advances in pharmacotherapy for alcohol dependence and abuse.

A researcher at Wake Forest University School of Medicine is shaking up the alcohol abuse research community with new findings that add to the complexity of the mechanism by which alcohol exerts its effects on the brain. In recognition of his work, Jeffrey Weiner, Ph.D., was presented the 2001 Young Investigator’s Award last month at the Research Society on Alcoholism’s meeting in San Francisco.

Weiner, an assistant professor of physiology and pharmacology at Wake Forest, presented his findings during a plenary session at the meeting. Having presented the research at meetings and as abstracts, he is now preparing a paper for peer-reviewed publication.

For years researchers have suspected that ethanol exerts its generally sedating effects on the brain through the same mechanism of action as other drugs that sedate the central nervous system, such as benzodiazepines or barbiturates, and many drugs used in anesthesia. These drugs are all known to interact with the brain’s primary inhibitory synapse, which uses the neurotransmitter gamma amino butyric acid, or GABA. By modulating the function of the GABA synapse, these drugs increase inhibition in the brain, slowing down nerve signals and therefore central nervous system function, leading in various degrees to mild sedation, sleep, deep anesthesia, and even coma or death.

"The funny thing about alcohol, though," Weiner told Psychiatric News, "is that it is by far the most widely used drug of abuse and has been studied by modern science for well over 100 years. Yet we still do not really know anything about it."

What made Weiner’s work unique was that instead of focusing on alcohol’s effects on the binding of GABA to receptors on the postsynaptic, or far, side of the synapse, he also looked at the effects of alcohol on the presynaptic, or near, side of the synapse.

"Unless you really focus on all of these mechanisms, you don’t get the full picture of what alcohol is doing," Weiner emphasized. "By looking at both presynaptic and postsynaptic actions, we discovered a whole new way that the sensitivity of the synapse to alcohol is regulated."

Weiner looked at GABA synapses in the rat hippocampus and focused his attention on two receptors that bind the neurotransmitter: the GABA-A receptor, known to be the major receptor in inhibitory synapses (making up about 30 percent to 40 percent of the total synapses in the brain) and the GABA-B receptor.

GABA-A receptors, Weiner explained, are located on both the pre- and postsynaptic sides of the inhibitory synapse and, when bound by GABA, inhibit transmission of nerve impulses across the synapse. GABA-B receptors are found only on the presynaptic side, and Weiner said that they are thought to be involved in a feedback mechanism.

"We think they are there to sense the amount of GABA in the synapse that is sort of back-flowing to the presynaptic side," he said. "Once they are bound by GABA, they inhibit any further release of GABA."

Previous research had shown that alcohol has more robust sedating effects if the GABA-B receptors are blocked by an antagonist drug, therefore shutting down the feedback loop. Weiner’s current research significantly expands on that view.

"What we think is going on," Weiner explained, "is that alcohol is doing something to enhance the GABA-A receptor mechanism—we’re not 100 percent sure exactly what it is, but the key is that, at the same time, it is also interacting with the GABA-B receptors on the presynaptic side and enhancing their function. So what you really get is a balance of the two effects. And that we think is what accounts for the extreme variability in individual sensitivity to alcohol and the extreme tolerance to the drug that exists."

The average drink, Weiner noted, contains about 12 gms of alcohol, compared with milligrams of the average drug that interacts with GABA synapses.

What could be occurring, Weiner told Psychiatric News, is that the interaction of alcohol with the GABA-B receptor boosts the natural feedback mechanism, limiting the overall effect of alcohol at the synapse.

"This doesn’t happen with benzodiazepines and barbiturates," he said. "They couldn’t care less whether or not the GABA-B mechanism is there or not."

In his experiments, Weiner used an old drug, baclofen (Lioresal)—a known GABA-B agonist—to prove his point. Baclofen had no effect on the actions of either benzodiazepines or barbiturates, but when used in common with alcohol, baclofen bound to the GABA-B receptors completely blocked the GABA-A response to alcohol.

"In Europe, studies have been under way looking at GABA-B agonists to treat alcohol craving and alcohol withdrawal, with fairly good results," Weiner said. Weiner added that if others are able to replicate his results, the findings could explain why the drugs might be efficacious in alcohol treatment and, in the long term, lead to a new option for patients.

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