GABAA subtype-specific pharmacological modulation of reward-related behavior

描述（由申请人提供）：人类遗传学研究是否存在编码GABAA受体的相关基因？精神疾病的亚单位，如严重抑郁症，双相情感障碍，精神分裂症，酒精依赖和非法药物依赖。然而，这些基因的产物在抑郁样行为和滥用潜力方面的功能尚不清楚。在此应用中，我们建议研究不同的GABAA受体亚型定义的存在下的作用？1、？2还是？使用颅内自我刺激范例的奖励相关行为中的3个亚基。地西泮（ValiumR），一种非亚型选择性苯二氮卓类药物，可降低奖赏阈值，然而，介导该作用的GABAA受体亚型尚不清楚。唑吡坦（AmbienR）的影响，部分？1-选择性催眠剂--如地西泮--也是在奖赏下自我给药的，还没有被研究过。我们假设？1-在腹侧被盖区的GABA能中间神经元上含有GABAA受体，2-含有GABAA受体的GABA能神经元在脑桥核介导的奖励阈值的降低（“抗抑郁样”行动），而？3-在腹侧被盖区的多巴胺能神经元中含有GABAA受体的化合物介导奖赏阈值的增加（“促兴奋样作用”）。使用携带点突变的基因敲入小鼠？1、？2，或？3亚基，使各自的GABAA受体不敏感的地西泮和唑吡坦调制，我们将剖析个别受体亚型的贡献，这些药物的奖励调节作用。调节奖赏相关行为的GABAa受体亚型的鉴定与新型抗抑郁药物的开发以及新型亚型选择性化合物（例如用于治疗焦虑症、失眠或慢性疼痛）的依赖性和滥用倾向的预测相关，所述预测基于对限定的GABAa受体亚型的特异性功效。公共卫生相关性：该项目将研究中脑边缘多巴胺系统中表达的三种GABAA受体亚型在奖励相关行为中的作用，并假设一些GABAA受体亚型将减少奖励，而另一些将增强奖励。奖赏增强型GABAa受体亚型的特异性激动剂可能适合于治疗抑郁症，而奖赏降低型GABAa受体亚型的特异性激动剂可能适合于治疗躁狂发作。此外，由于目前正在开发GABAa受体亚型选择性药物用于治疗焦虑、失眠和慢性疼痛，因此了解单个GABAa受体亚型的奖赏调节功能对于设计具有低滥用倾向的化合物将是重要的。

DESCRIPTION (provided by applicant): Human genetic studies have linked genes encoding GABAA receptor ? subunits to mental illnesses like major depression, bipolar disorder, schizophrenia, alcohol dependence, and illicit drug dependence. However, the functions of the products of these genes with respect to depressive-like behavior and abuse potential are unknown. In this application, we propose to study the role of different GABAA receptor subtypes defined by the presence of the ?1, ?2 or ?3 subunits in reward-related behavior using the intracranial self-stimulation paradigm. Diazepam (ValiumR), a non-subtype-selective benzodiazepine decreases the reward threshold, however, the GABAA receptor subtype mediating this action is unknown. The effects of zolpidem (AmbienR), a partially ?1-selective hypnotic agent that - like diazepam - is also self-administered on reward have not been examined. We hypothesize that ?1- containing GABAA receptors on GABAergic interneurons in the ventral tegmental area and ?2-containing GABAA receptors on GABAergic neurons in the nucleus accumbens mediate a decrease of the reward threshold ("antidepressant-like" action), while ?3-containing GABAA receptors in dopaminergic neurons of the ventral tegmental area mediate an increase in the reward threshold ("pro-depressant-like action"). Using knock-in mice carrying point mutations in the ?1, ?2, or ?3 subunit rendering the respective GABAA receptors insensitive to modulation by diazepam and zolpidem, we will dissect the contribution of individual receptor subtypes to the reward-modulating action of these agents. The identification of the GABAA receptor subtypes regulating reward-related behaviors is of relevance for the development of novel antidepressant drugs and also for the prediction of the dependence and abuse liability of novel subtype-selective compounds, e.g. for the treatment of anxiety disorders, insomnia or chronic pain, based on specific efficacy at defined GABAA receptor subtypes. PUBLIC HEALTH RELEVANCE: The proposed project will investigate the roles of three GABAA receptor subtypes which are expressed in the mesolimbic dopamine system in reward-related behavior with the hypothesis that some GABAA receptor subtypes will be reward-reducing while others will be reward-enhancing. Specific agonists at reward- enhancing GABAA receptor subtypes might be suitable for the treatment of depression, whereas specific agonists at reward-reducing GABAA receptor subtypes might be suitable for the treatment of manic episodes. Moreover, as GABAA receptor subtype-selective agents are currently being developed for the treatment of anxiety, insomnia, and chronic pain, knowledge on the reward-modulating functions of individual GABAA receptor subtypes will be important for the design of compounds with a low abuse liability.