UC San Francisco researchers have identified an enzyme that could prove to be atarget for reducing the craving for, and excessive use, of alcohol - a hallmarkof alcoholism.
In the November issue of Nature Neuroscience, they report that mice geneticallyengineered to lack the enzyme, known as PKC , were 75 percent less apt toimbibe than their normal brethren.
Mice lacking the enzyme also responded as if they were pre-treated with a classof drugs that are commonly used to treat seizures, anxiety and epilepsy, butshowed now sign of being sleepy or sedate, normally a side effect of thedrugs. The finding suggests that inhibiting PKC activity could also improve,or supplant, these existing drugs, the researchers said.
The explanation for the findings is that the absence of PKC enhances theeffects of alcohol and the other drugs, known as benzodiazepines, on amolecular receptor in the brain known as GABA-A. The GABA-A receptor is themolecular channel through which most signals telling the brain to feelgratified or relaxed or sedated - all messages of "inhibition" -- arecommunicated.
Normally, the GABA-A receptor is regulated by a chemical messenger known as theGABA-A neurotransmitter. When the neurotransmitter is fired from one neuron, itlatches onto the receptor site in the membrane of a target cell and there, likea latchkey, opens the receptor's channel, allowing chloride ions containingsignals of inhibition to flow through to a receptive neuron. The result is aflood of gratification, relaxation or sedation (depending on the signals) inthe central nervous system.
Alcohol and benzodiazepines, which latch on to an adjacent spot on the GABA-Areceptor, act by enhancing the response of the receptor to the GABAneurotransmitter, prompting the receptor to keep its channel open longer thannormal, which leads to the release of more signals of gratification, relaxationor sedation.
The UCSF study demonstrates that, without PKC, but in the presence of alcoholor the other drugs, the GABA-A receptor becomes even more sensitive to the GABAneurotransmitter, responding, in a sense, like a hair trigger. The outcome isthat the receptor keeps its channel open even longer, allowing still moresignals of inhibition to flow into the central nervous system.
The increased sensitivity to alcohol in the absence of PKC was dramatized inthe animals' behavior after they took a nip. Mice lacking PKC became twice asactive in response to low doses of alcohol (dashing around their cages) thannormal mice. And they became more sedated in response to high doses (takinglonger to awaken) than normal animals. (These findings were in keeping withthe curiously contrasting effects of alcohol at low and high doses.)
The findings were also observed in brain cells, with the GABA-A receptorresponding to lower doses of alcohol and benzodiazepines in genetically alteredmice than in normal mice.
And it is this increased sensitivity, said Clyde Hodge, PhD, a UCSF assistantprofessor of neurology and an investigator at the Ernest Gallo Clinic andResearch Center at UCSF, that decreases the animals' craving for alcohol.
"These mice support the concept emerging in alcohol research that increasedsensitivity to alcohol intoxication lessens the likelihood that a person willbecome an alcoholic," Hodge said.
A long-running UC San Diego study of sons of alcoholics illustrates the theoryin humans. The ongoing trial, conducted by UCSD researcher Mark A. Schuckit,MD, UCSD professor of psychiatry, shows that those sons who were more sensitiveto alcohol's effects as teenagers were less likely to become alcoholics asadults.
The UCSF results may suggest, said the researchers, that mutations in the genefor the PKC enzyme may influence the susceptibility of certain individuals tobecoming alcoholics. However, it's just as likely, they said, that they havesimply identified a mechanism for disrupting normally occurring molecularactivity at the GABA receptor.
"It's possible that PKC's impact on the GABA receptor in response to alcoholand other drugs is simply a biochemical phenomenon that will give us a handleon making new drugs to regulate the GABA receptor," said co-author RobertMessing, MD, UCSF associate professor of neurology and an investigator at theErnest Gallo Clinic and Research Center at UCSF.
"Pharmacological agents that inhibit PKC might prove useful for treatingalcoholism and provide a non-sedating alternative for enhancing GABA-A receptorfunction in therapy of other disorders, such as anxiety and epilepsy," Messingsaid.
On a more fundamental level, the UCSF finding offers an important insight intothe complex regulation of the key receptor for signals of gratification,relaxation and sedation in the central nervous system. Scientists have knownfor some time that alcohol and benzodiazepines act by enhancing the effect ofthe GABA neurotransmitter on its receptor and that these so-called "allostericmodulators" do so by latching on to a site adjacent to the key activation siteon the GABA receptor. The new finding suggests that PKC, one of at least 10known forms of the ubiquitous PKC enzyme, plays a role in restraining the GABAreceptor's sensitivity to these inciting factors.
And this, said Messing, represents "a unique kind of modulation." PKC enzymesact by "phosphorylating," or adding a phosphate group, to receptors. In thiscase, the impact of phosphorylation appears to be dampening the brain'sresponse to alcohol.
Other co-authors of the UCSF study were Kristin K. Mehmert, BS, Stephen P.Kelley, MS, Thomas McMahon, BS, and Ashley Haywood, BA, all staff researchassociates; M. Foster Olive, PhD, senior scientist, Dan Wang, MD, MS, staffresearch associate, and Ana Maria Sanchez-Perez, PhD, post-doctoral fellow, allinvestigators at the Ernest Gallo Clinic and Research Center at UCSF.
The study was funded by the State of California for Alcohol and Drug AbuseResearch, and the Alcoholic Beverage Medical Research Foundation.
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