The goal of this proposal is to determine the role of alpha 1 containing GABA type A receptors, GABA(A)-Rs, in ethanol-induced tolerance and dependence. GABA(A)-Rs may be especially important moleculartargets for some behavioral effects of ethanol. However,the role of individual GABA(A)-R subtypes in ethanol- induced behavioral effects is unclear. Previous studies suggest alphal GABA(A)-Rs may be involved in ethanol-induced tolerance and dependence, two factorsthought to contribute to alcoholism. To assess the role of this receptor subunit in ethanol action, genetically modified mice with ethanol-insensitive, but otherwise normal alpha 1 GABA(A)-Rs have been created. Using this knockin mouse model, tolerance to chronic ethanol exposure on ethanol-induced hypnosis, ataxia, anxiolysis and analgesia will be assessed. Similarly, the role of alpha 1 in dependence will be assessedby measuring handling-induced convulsions, anxiety and hyperalgesia during ethanol withdrawal. Ultimately, understanding the molecular basis of tolerance and dependence may lead to better methods for treatment of alcohol abuse and alcoholism.
