GABAA subtype-specific pharmacological modulation of reward-related behavior

GABAA 亚型特异性奖赏相关行为的药理调节

基本信息

批准号：
7739969
负责人：
Uwe Rudolph
金额：
$ 7.9万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7739969
关键词：
Adverse effects Agonist Alcohol dependence Alcohols Alprazolam Anhedonia Animals Antidepressive Agents Anxiety Anxiety Disorders Behavior Benzodiazepines Bipolar Disorder Cells Clinical Data Dependence Development Diazepam Drug Addiction Drug Design Drug abuse Drug effect disorder Future GABA Agents Genes Human Human Genetics Illicit Drugs Individual Interneurons Knock-in Mouse Knowledge Lead Ligands Link Major Depressive Disorder Manic Mediating Mental disorders Methods Moods Motivation Mus Mutate Neurons Nucleus Accumbens Pharmaceutical Preparations Point Mutation Population Property Proteins Rattus Reporting Rewards Role Schizophrenia Self Stimulation Self-Administered Signal Transduction Site Sleeplessness Unipolar Depression Variant Ventral Tegmental Area Wild Type Mouse Work base chronic pain depression depressive symptoms design dopaminergic neuron experience gamma-Aminobutyric Acid hypnotic median forebrain bundle mesolimbic system novel public health relevance receptor research study zolpidem

项目摘要

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.

描述（由申请人提供）：人类遗传研究已将编码GABAA受体的基因联系起来？精神疾病的亚基，例如严重抑郁症，躁郁症，精神分裂症，酒精依赖和非法药物依赖。但是，这些基因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，我们建议研究使用颅内自我刺激范式在与奖励相关行为中存在的不同GABAA受体亚型的作用。地西epa（valiumr），一种非辅助选择性苯二氮卓类药物降低了奖励阈值，但是，介导此动作的GABAA受体亚型尚不清楚。尚未检查Zolpidem（Ambienr）（Ambienr），一种部分？1一种选择性的催眠剂，就像地西ep剂一样，也没有被检查。 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调解奖励阈值的增加（“类似抑郁剂的动作”）。使用敲入小鼠在？1，？2或？3亚基中使用地西ep和Zolpidem对各自的GABAA受体对调节不敏感的亚基，我们将剖析单个受体亚型对这些剂的奖励调节作用的贡献。调节与奖励相关行为的GABAA受体亚型的鉴定与新型抗抑郁药的开发以及预测新型亚型选择性化合物的依赖性和滥用责任相关。为了治疗焦虑症，基于定义的GABAA受体亚型的特异性功效。公共卫生相关性：拟议的项目将调查三种GABAA受体亚型的作用，它们在与奖励相关的行为中在奖励相关的行为中表达，并假设某些GABAA受体子类型将是奖励的，而其他人则将是奖励的奖励。奖励增强GABAA受体亚型的特定激动剂可能适合治疗抑郁症，而减少奖励GABAA受体亚型的特定激动剂可能适合治疗躁狂发作。此外，由于目前正在开发GABAA受体亚型选择剂来治疗焦虑，失眠和慢性疼痛，因此对单个GABAA受体亚型的奖励调节功能的知识对于设计具有低滥用责任的化合物的设计很重要。