The Role of GABA A Receptor Subtypes in Benzodiazepine Abuse Liability

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DESCRIPTION (provided by applicant): Benzodiazepines are among the most widely abused drugs, and like other drugs of abuse, they "hijack" the brain's dopaminergic reward system, in which several GABAA receptor subtypes are expressed in different neuronal cell types. The modulation of the reward system and of benzodiazepine self-administration by distinct GABAA receptor subtypes is only poorly understood. Here, we want to test the hypothesis that GABAA receptors bidirectionally modulate these behaviors. In the absence of chemical compounds which are truly specific for a GABAA receptor subtype, we propose to use a novel combined genetic and pharmacological approach to create a model system which will enable highly specific modulation of the activity of individual GABAA receptor subtypes. This will be achieved by using the non- selective benzodiazepine drugs diazepam and midazolam in triple point-mutated mice, in which these drugs are a true ?1-specific, ? 2-specific, ? 3-specific, or ? 5-specific full agonists, respectively. This system will make it possible to test whether potentiatio of a particular GABAA receptor subtype is sufficient for reward enhancement and benzodiazepine self-administration.