Currently, almost 20 million Americans meet the diagnostic criteria necessary for alcoholism. Alcoholism is a complex disease of chronic alcohol consumption that encompasses both genetic and environmental factors. Although alcohol negatively affects all organ systems, the addictive manifestations are mediated through the CNS. The lack of effective treatments for alcoholism has resulted in a more focused approach at locating highly selective ethanol targets with the goal of the development of improved therapeutics. Studies implicate GABAA receptors in the both behavioral effects of and susceptibility to alcoholism. Although there is strong evidence for molecular sites of alcohol action on GABA receptors that have been correlated with behavioral studies, alcohol effects on synaptic receptors often require supra- physiologically relevant alcohol concentrations to produce moderate receptor modulation. This, along with findings obtained from molecular screenings of alcohol sites on structurally-related receptors, has led to my hypothesis that multiple and opposing alcohol interaction sites may be present. This work proposes that an additional high affinity alcohol site exists that opposes known alcohol interaction sites on GABAA receptors. Results from this work will provide a novel model of alcohol inhibition on GABAA receptors, a possible explanation for the diverse actions of alcohol on subpopulations of these receptors and may reveal important information on the structure-function of these receptors.
Although alcohol has been used for both social and medicinal purposes for many years, a complete understanding of its action on the brain is not well understood. The purpose of this work is to gain a better understanding on how alcohol affects the brain through its discrete interaction(s) with receptor proteins.
| Johnson 2nd, W David; Howard, Rebecca J; Trudell, James R et al. (2012) The TM2 6' position of GABA(A) receptors mediates alcohol inhibition. J Pharmacol Exp Ther 340:445-56 |
