The Role of GABA A Receptor Subtypes in Benzodiazepine Abuse Liability

描述（由申请人提供）：苯二氮卓类药物是滥用最广泛的药物之一，与其他滥用药物一样，它们“劫持”了大脑的多巴胺能奖励系统，其中几种GABAA受体亚型在不同的神经细胞类型中表达。不同GABAA受体亚型对奖励系统和苯二氮卓类药物自我给药的调节知之甚少。在这里，我们想要验证GABAA受体双向调节这些行为的假设。在缺乏真正特异性GABAA受体亚型的化合物的情况下，我们建议使用一种新的结合遗传和药理学的方法来创建一个模型系统，该模型系统将能够高度特异性地调节单个GABAA受体亚型的活性。这将通过在三点突变小鼠中使用非选择性苯二氮卓类药物地西泮和咪达唑仑来实现，其中这些药物是真正的？这个例子,?2-specific, ?3特异性的，还是？5种特异性的完全激动剂。该系统将有可能测试特定GABAA受体亚型的增强是否足以增强奖励和苯二氮卓类药物的自我给药。

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. PUBLIC HEALTH RELEVANCE: The neurobiological mechanisms underlying benzodiazepine abuse are not well understood, and in particular, the roles of the individual GABAA receptor subtypes in reward-related and self-administration behaviors are largely unknown. We propose to examine whether any of the major four benzodiazepine- sensitive GABAA receptor subtypes is sufficient for modulation of these behavioral responses and plan to demonstrate that GABAA receptors bidirectionally modulate these processes. The knowledge of how each of these GABAA receptor subtypes affects the abuse potential of benzodiazepines is relevant for the development of GABAA receptor subtype-selective compounds for the treatment of anxiety, chronic pain, cognitive deficits, and of benzodiazepine abuse.