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发现编码GABAA受体的相关基因？精神疾病的亚基，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，这些基因的产物在抑郁样行为和虐待潜力方面的功能尚不清楚。在本应用中，我们拟研究由？1, ?2还是？使用颅内自我刺激范式的奖励相关行为中的3个亚单位。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，然而，介导这一作用的GABAA受体亚型尚不清楚。唑吡坦（AmbienR）的作用，部分？选择性催眠剂——像地西泮一样——也是自我给予奖励的，还没有被研究过。我们假设？腹侧被盖区gaba能中间神经元上1-含GABAA受体伏隔核GABAA能神经元上含有2的GABAA受体介导了奖励阈值的降低（“抗抑郁样”作用），而？腹侧被盖区多巴胺能神经元中含有3- GABAA受体介导奖赏阈值的增加（“促抑郁样作用”）。使用携带点突变的敲入小鼠？1, ?2，还是？3个亚基使各自的GABAA受体对地西泮和唑吡坦的调节不敏感，我们将剖析个体受体亚型对这些药物的奖励调节作用的贡献。鉴定调节奖励相关行为的GABAA受体亚型与开发新型抗抑郁药物相关，也与预测新型亚型选择性化合物的依赖和滥用倾向相关，例如，基于特定GABAA受体亚型的特异性疗效，用于治疗焦虑症、失眠或慢性疼痛。公共健康相关性：该项目将研究在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受体亚型会减少奖励，而另一些则会增加奖励。奖励增强型GABAA受体亚型的特异性激动剂可能适用于治疗抑郁症，而奖励减少型GABAA受体亚型的特异性激动剂可能适用于治疗躁狂发作。此外，由于GABAA受体亚型选择性药物目前正在开发用于治疗焦虑、失眠和慢性疼痛，了解个体GABAA受体亚型的奖励调节功能对于设计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.