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Source: Jennifer O'Brien
415-476-2557
19 October 1999
ABSTEMIOUS MICE OFFER HINT AT MOLECULAR TARGET FOR TREATING ALCOHOLISM
Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have identified an enzyme that could prove to be a target for reducing the craving for, and excessive use of, alcohol - a hallmark of alcoholism.
In the November issue of Nature Neuroscience, they report that mice genetically engineered to lack the enzyme, known as PKC , were 75 percent less apt to imbibe than their normal brethren.
Mice lacking the enzyme also responded as if they were pre-treated with a class of drugs that are commonly used to treat seizures, anxiety and epilepsy, but showed no sign of being sleepy or sedate, normally a side effect of the drugs, suggesting a target for improving or supplanting existing drugs, the researchers said.
The explanation for the findings is that the absence of PKC enhances the effects of alcohol and the other drugs, known as benzodiazepines, on a molecular receptor in the brain known as GABA-A. The GABA-A receptor is the molecular channel through which most signals telling the brain to feel gratified or relaxed or sedated - all messages of "inhibition" -- are communicated.
Normally, the GABA-A receptor is regulated by a chemical messenger known as the GABA neurotransmitter. When the neurotransmitter is fired from one neuron, it latches onto the receptor site in the membrane of a target cell and there, like a latchkey, opens the receptor's channel, allowing chloride ions containing signals of inhibition to flow through to a receptive neuron. The result is a flood of gratification, relaxation or sedation (depending on the signals) in the central nervous system.
Alcohol and benzodiazepines, which latch on to an adjacent spot on the GABA-A receptor, act by enhancing the response of the receptor to the GABA neurotransmitter, prompting the receptor to keep its channel open longer than normal, which leads to the release of more signals of gratification, relaxation or sedation.
The UCSF study demonstrates that, without PKC, but in the presence of alcohol or the other drugs, the GABA-A receptor becomes even more sensitive to the GABA neurotransmitter, responding like a hair trigger. The outcome is that the receptor keeps its channel open even longer, allowing still more signals of inhibition to flow into the central nervous system.
And it is this increased sensitivity, said Clyde Hodge, PhD, a UCSF assistant professor of neurology and an investigator at the Ernest Gallo Clinic and Research Center at UCSF and the Wheeler Center for the Neurobiology of Addiction at UCSF, that decreases the animals' craving for alcohol.
"These mice support the concept emerging in alcohol research that increased sensitivity to alcohol intoxication lessens the likelihood that a person will become an alcoholic," Hodge said.
A long-running VA and UC San Diego study of sons of alcoholics illustrates the theory in humans. The ongoing trial, conducted by UCSD researcher Marc A. Schuckit, MD, UCSD professor of psychiatry, shows that those sons who were more sensitive to alcohol's effects as teenagers were less likely to become alcoholics as adults.
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