GABAA subtype-specific pharmacological modulation of reward-related behavior

描述(申请人提供)：人类遗传学研究是否与编码GABAA受体的基因有关？精神疾病的亚单位，如严重抑郁症、躁郁症、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。在这个应用中，我们建议使用颅内自我刺激范式来研究不同的GABAA受体亚型在奖赏相关行为中的作用，这些亚型由？1、？2或？3亚基的存在所定义。地西潘(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)是一种部分？1-选择性催眠药，与安定一样，也是自我给予的奖励药物，其效果尚未得到检验。我们推测，腹侧被盖区GABA能中间神经元上含有β1受体的GABA AA受体和伏核GABA能神经元上含有GAAA受体的β2受体介导了奖赏阈值的降低(“抗抑郁药样”作用)，而腹侧被盖区多巴胺能神经元上含有β3受体的GAAA受体介导了奖赏阈值的升高(“促抑郁药样作用”)。利用携带？1、？2或？3亚单位点突变的敲入小鼠，使各自的GABAA受体对安定和唑吡坦的调制不敏感，我们将剖析个别受体亚型对这些药物的奖赏调节作用的贡献。识别调节奖赏相关行为的GABAA受体亚型对于开发新的抗抑郁药物以及基于特定GABAA受体亚型的特定疗效预测新的亚型选择性化合物的依赖和滥用倾向具有重要意义，例如用于治疗焦虑症、失眠或慢性疼痛。与公共健康相关：该项目将研究在中脑边缘多巴胺系统中表达的三种GABAA受体亚型在奖赏相关行为中的作用，假设一些GABAA受体亚型将是奖赏减少，而另一些亚型将是奖赏增强。奖励增强型GABAA受体亚型的特异性激动剂可能适合于抑郁症的治疗，而奖励减少型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.