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A team of scientists at The Scripps Research Institute has described the cellular mechanism underlying the brain's response to alcohol, which suggests a possible method for treating alcoholism.

This work, published in the latest issue of the journal Science, ties together the effect of the brain peptide corticotropin releasing factor (CRF) with alcohol. Both appear to influence neurotransmission in the amygdala, the so-called pleasure center of the brain, by increasing the transmission of one particular neurotransmitter called gamma amino butyric acid (GABA).

"There is a strong relationship between drugs of abuse, stress, and the amygdala," says Neuropharmacology Professor George Siggins, who led the research.

The research suggests that compounds that block CRF receptors might be a potential new therapeutic for alcoholics, who struggle to stop drinking.

Drugs that block CRF receptors are already being looked at by scientists as potential treatments for other psychiatric conditions such as depression, panic disorder, and post-traumatic stress disorder--conditions that also involve CRF in the amygdala.

In the latest research, Siggins and his colleagues looked at the effect of alcohol and a common stress-related neuropeptide on a neurotransmitter called gamma amino butyric acid (GABA).

GABA is the main inhibitory neurotransmitter in the brain, and neurons in every brain region use GABA to fine-tune signaling throughout the nervous system.

Scientists have known for several years that alcohol produces many of its intoxicating actions through facilitation of GABA receptor function, and preclinical studies of alcohol dependence have shown that GABAergic activity decreases during alcohol withdrawal and protracted abstinence--the initial post-acute withdrawal period after the cessation of drinking during which a person is especially vulnerable to relapse. These GABAergic activity changes are probably a major cause of relapse to alcoholism in individuals undergoing treatment.

Previous studies have also shown that alcohol enhances GABA neurotransmission in the amygdala, the so-called pleasure center of the brain. Interestingly, the brain corticotropin releasing factor (CRF) stress system also increases GABA transmission in the amygdala.

CRF is a common peptide in the brain that is responsible for activating the hypothalamic-pituitary-adrenal stress response and in the amygdala for activating sympathetic and behavioral responses to stressors. CRF is found in lots of different parts of the brain and is known to be involved in the brain in response to stress, anxiety, and depression.

Significantly, the CRF system also seems to be central to alcoholism, and scientists at Scripps Research and elsewhere have shown that CRF is involved in the transition from alcohol use to alcohol dependence. Scripps Research Professor George Koob and his colleagues found recently that levels of CRF increase in brains treated with alcohol. Other studies have shown that CRF levels increase when animals are withdrawing from alcohol as well--a situation analogous to an alcoholic's protracted abstinence.

In their latest paper, Siggins and his colleagues show, at the cellular level, how alcohol and CRF interact. When neurons are exposed to alcohol, says Siggins, they release CRF, and this causes the release of GABA in the amygdala. And when the CRF receptor is removed altogether (by genetic knock out), the effect of alcohol and CRF on GABA neurotransmission is lost.

Siggins and his colleagues say that this suggests a cellular mechanism underlying involvement of CRF in alcohol's behavioral and motivational effects. During withdrawal, CRF levels increase and these changes may persist for a long time.

It also suggests a possible way of treating alcoholism -- using CRF antagonists, or compounds that block the effects of CRF. In the current study, when the scientists applied an antagonist of CRF, they found that alcohol no longer had an effect.

"Not only did the antagonists block the effect of CRF in enhancing GABA transmission, it also blocked the effect of alcohol," says Siggins. "The response was totally gone­alcohol no longer did anything."

http://alcoholism.about.com/cs/effect/a/blscr040304.htm