GABAA subtype-specific pharmacological modulation of reward-related behavior

描述（由申请人提供）：人类遗传学研究已将编码 GABAA 受体的基因联系起来？精神疾病的亚单位，如重度抑郁症、双相情感障碍、精神分裂症、酒精依赖和非法药物依赖。然而，这些基因产物在抑郁样行为和虐待潜力方面的功能尚不清楚。在此应用中，我们建议使用颅内自我刺激范式研究由 ?1、?2 或 ?3 亚基的存在定义的不同 GABAA 受体亚型在奖励相关行为中的作用。地西泮 (ValiumR) 是一种非亚型选择性苯二氮卓类药物，可降低奖赏阈值，但介导此作用的 GABAA 受体亚型尚不清楚。唑吡坦 (AmbienR) 是一种部分 β1 选择性催眠药，与地西泮一样，也可自行给药以奖励奖赏，其效果尚未得到研究。我们假设腹侧被盖区 GABA 能中间神经元上含有 ?1 的 GABAA 受体和伏隔核 GABA 能神经元上含有 ?2 的 GABAA 受体介导奖赏阈值的降低（“抗抑郁样”作用），而腹侧被盖区多巴胺能神经元中含有 ?3 的 GABAA 受体介导奖赏阈值的增加（“类似促抑郁剂的作用”）。使用在α1、β2或β3亚基中携带点突变的敲入小鼠，使各自的GABAA受体对地西泮和唑吡坦的调节不敏感，我们将剖析各个受体亚型对这些药物的奖赏调节作用的贡献。调节奖赏相关行为的 GABAA 受体亚型的鉴定对于新型抗抑郁药物的开发以及新型亚型选择性化合物的依赖性和滥用倾向的预测具有重要意义。基于对特定 GABAA 受体亚型的特定功效，用于治疗焦虑症、失眠或慢性疼痛。公共健康相关性：拟议项目将研究中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，假设某些 GABAA 受体亚型会减少奖励，而另一些则会增加奖励。奖励增强的 GABAA 受体亚型的特异性激动剂可能适合治疗抑郁症，而奖励减少的 GABAA 受体亚型的特异性激动剂可能适合治疗躁狂发作。此外，由于目前正在开发用于治疗焦虑、失眠和慢性疼痛的 GABAA 受体亚型选择性药物，因此了解个体 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非常重要。

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.