Pharmacogenetics is a discipline that seeks to elucidate the contribution of genetic factors to individual differences in drug responses. The related discipline, behavioral pharmacogenetics, stems from the realization that behavioral responses to drugs are in principle no different from physiological or biochemical responses. This approach has culminated in genetic selection of lines of rodents for differences in acute sensitivity to ethanol. These genetically defined populations of animals provide a useful tool for testing hypotheses about the biochemical mechanisms that underlie the selected differences in behavioral sensitivity to ethanol. There is now considerable evidence that acute exposure to ethanol enhances the opening of GABA-operated chloride channels. We have demonstrated and pharmacologically characterized a technique that allows for the direct measure of GABA-mediated chloride influx in brain membrane vesicles. Using this technique we have found rodents who are sensitive to the depressant effects of ethanol behaviorally, are also sensitive to ethanol-induced increases in GABA-mediated chloride flux compared to their ethanol resistant selection counterparts. Ethanol sensitive animals were also found more sensitive to augmentation of GABA-mediated chloride flux by benzodiazepires, but not more sensitive to the GABA agonist, muscimol or to pentobarbital. There appears to be a close relationship (both in vivo and in vitro) between sensitivity to ethanol and benzodiazepines. In contrast, sensitivity to these two drugs is not closely -related to sensitivity to other agents acting on the chloride channel complex such as GABA agonists, pentobarbital or convulsants. The proposed research will define the role of the GABA/Benzodiazepine receptor chloride channel complex in the expression and inheritance of ethanol sensitivity using behavioral pharmacogenetic and classical Mendelian genetic techniques. It is anticipated that these studies will provide insight in to the neural and genetic mechanisms responsible for ethanol sensitivity.
