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 molecular targets 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 factors thought 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 assessed by 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. ? ? ?
