Antidepressant-like and reward-related functions of a2-containing GABAA receptors

描述（由申请人提供）：这是一份资助研究a2-含GABAA受体在抑郁症动物模型中的作用的申请。先前已经证明，显示gaba能抑制减少的小鼠（32只小鼠）显示出一种令人联想到抑郁症的表型。目前尚不清楚哪些GABAA受体亚型介导抗抑郁样作用，而我们最近获得的初步数据表明，含有13的GABAA受体介导抗抑郁样作用。腹侧被盖区多巴胺能神经元主要表达含有a3的GABAA受体，而伏隔核的GABAA能神经元主要表达含有a2的GABAA受体。利用缺乏a2亚基的小鼠，我们想要验证含有a2的GABAA受体在基于绝望的强迫游泳测试、基于冲突的新奇抑制喂养测试和基于奖励的颅内自我刺激范式中介导抗抑郁样作用的假设。GABAA受体亚型与抗抑郁样作用的鉴定将代表着理解情绪调节的重要进展，并将为开发新型抗抑郁药物提供新的途径。抑郁症和相关情绪障碍是最严重的公共卫生问题之一；严重形式的抑郁症影响了2-5%的美国人口，高达20%的人口患有轻度形式的抑郁症。抑郁症的症状包括体验奖励的能力降低（快感缺乏）、烦躁不安、焦虑和绝望，而且相当多的患者对目前的治疗方案反应不满意。鉴定含有a2的GABAA受体具有抗抑郁，特别是奖励增强功能，将确定该受体亚型作为开发具有新型作用机制的抗抑郁药的靶标。

DESCRIPTION (provided by applicant): This is an application for funding of a study examining the role of a2-containing GABAA receptors animal models of depression. It has been shown previously that mice which display reduced GABAergic inhibition (32 mice) display a phenotype reminiscent of depression. It is not known which GABAA receptor subtypes mediate antidepressant-like actions, while we have recently obtained preliminary data suggesting that 13-containing GABAA receptors mediate prodepressant-like actions. Whereas dopaminergic neurons in the ventral tegemental area express primarily a3-containing GABAA receptors, the GABAergic neurons in the nucleus accumbens primarily express a2-containing GABAA receptors. Using mice lacking the a2 subunit, we want to test the hypothesis that a2-containing GABAA receptors mediate an antidepressant-like action in the despair-based forced swim test, the conflict-based novelty-suppressed feeding test and the reward-based intracranial self-stimulation paradigm. The identification of the GABAA receptor subtype responsible for antidepressant-like effects would represent an important advance for understanding mood regulation and would provide a new avenue for the development of novel antidepressant agents. Depression and related mood disorders are among the greatest public health problems; severe forms of depression affect 2-5% of the U.S. population, and up to 20% of the population suffer from milder forms of the illness. Symptoms of depression include a reduced ability to experience reward (anhedonia), dysphoria, anxiety and despair, and a substantial number of patients do not respond satisfactorily to current treatment options. Identification of the a2-containing GABAA receptor as having antidepressant and in particular reward-enhancing functions would identify this receptor subtype as a target for the development of antidepressants with a novel mechanism of action.