The Role of GABA A Receptor Subtypes in Benzodiazepine Abuse Liability

描述（由申请人提供）：苯二氮卓类药物是最广泛滥用的药物之一，与其他滥用药物一样，它们“劫持”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元细胞类型中表达。不同GABAA受体亚型对奖赏系统和苯二氮卓类自我给药的调节知之甚少。在这里，我们想测试的假设，GABAA受体双向调节这些行为。在缺乏真正特异于GABAA受体亚型的化合物的情况下，我们建议使用一种新的遗传和药理学相结合的方法来创建一个模型系统，该系统将能够高度特异性地调节单个GABAA受体亚型的活性。这将通过使用非选择性苯二氮卓类药物地西泮和咪达唑仑在三重点突变小鼠中实现，其中这些药物是真正的？1、具体？2、具体？3、具体的，还是？5-特异性完全激动剂。该系统将使得有可能测试特定GABAA受体亚型的增强是否足以用于奖赏增强和苯二氮卓自我施用。

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.