GABA-A Receptor Mechanisms in Benzodiazepine Dependence

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Chronic benzodiazepine (BZ) use can result in tolerance, evident as a diminution in the characteristic behavioral effects of the drug,.aswell as physical dependence, evident by the occurance of awithdrawal syndrome. The proposed studies will investigate the extent to which different GABAA receptor subtypes play a role in tolerance development and withdrawal following chronic BZ treatment in rhesus monkeys. Specific Aim 1will evaluate the roles of specific GABAA/a receptor subtypes in characteristic BZ-induced behaviors, including ataxia, sedation, motor impairment, and muscle relaxation. Subsequently, Specific Aim 2 will evaluate tolerance to each of these behaviors following chronic administration of the conventional BZ alprazolam. Receptor subtype-preferring agonists and antagonists will be used to investigate the hypothesis that GABAA/a1 and GABAA/a5 receptor subtypes are critically involved in BZ tolerance and withdrawal. Understanding the role of GABAA receptor subtypes in tolerance and withdrawal following chronic BZ treatment should provide needed information for developing new BZ-type drugs with reduced liability for physical dependence.