Emotional regulation: Modeling GABA A receptor subtype specific agents in mice

描述（由申请人提供）：GABAA受体是临床使用的苯二氮卓类药物的靶标，它非选择性地调节多种GABAA受体亚型。虽然在基于功能丧失方法识别GABAA受体亚型的不同功能方面取得了一些进展，这为设计治疗焦虑症和抑郁症等中枢神经系统疾病的新方法提供了可能性，但到目前为止，还没有真正的亚型特异性化合物，因此限制了对单个GABAA受体亚型功能的可用信息。在这里，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（三点突变小鼠+非选择性药物地西泮），其中地西泮是真正的？这个例子,?2-specific, ?3特异性的，还是？5特异性的完全激动剂，能够高度选择性地调节特定GABAA受体亚型的活性，以确定这些受体亚型的生理和药理学功能，特别是在调节焦虑和抑郁相关行为方面。

DESCRIPTION (provided by applicant): GABAA receptors are the target of clinically used benzodiazepines, which modulate multiple GABAA receptor subtypes non-selectively. While some progress has been made in identifying differential functions of GABAA receptor subtypes based on loss of function approaches which opens up the possibility to design novel treatments for CNS diseases such as anxiety disorders and depression, until now truly subtype-specific compounds are not available, thus limiting the information that is available on the function of individual GABAA receptor subtypes. Here we propose to use a novel combined genetic and pharmacological approach to create a model system (triple point-mutated mice + the non-selective drug diazepam) in which diazepam is a true ?1-specific, ?2-specific, ?3-specific, or ?5-specific full agonist, respectively, enabling the highly selective modulation of the activity of specific GABAA receptor subtypes in order to define the physiological and pharmacological functions of these receptor subtypes, in particular in the regulation of anxiety- and depression-related behaviors.