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Emotional regulation: Modeling GABA A receptor subtype specific agents in mice

情绪调节：在小鼠中模拟 GABA A 受体亚型特异性药物

基本信息

批准号：
8242894
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：
2012
资助国家：
美国
起止时间：
2012-01-06 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242894
关键词：
Affect Agonist Amnesia Anhedonia Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Arginine Autonomic nervous system Behavior Behavioral Behavioral Model Benzodiazepines Biological Models Boxing Central Nervous System Diseases Development Diazepam Emotional Future GABA-A Receptor Genes Genetic Hippocampus (Brain)Histidine Hypnosis Individual Induced Hyperthermia Knock-in Mouse Knowledge Label Light Limbic System Locomotion Mediating Mental Depression Modeling Mood Disorders Motor Activity Mus Muscle relaxation phase Mutate Pharmaceutical Preparations Physiological Point Mutation Population Property Public Health Regulation Research Rewards Role Sedation procedure Seizures Specificity Stress Stress Tests Structure Swimming Synapses System Tail Suspension Testing base behavior test depressive symptoms design drug development dysphoria experience in vivo loss of function noradrenergic novel receptor receptor function research study tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): GABAA receptors are the target of clinically used benzodiazepines, which modulate multiple GABAA receptor subtypes non-selectively. While some progress has been made in identifying differential functions of GABAA receptor subtypes based on loss of function approaches which opens up the possibility to design novel treatments for CNS diseases such as anxiety disorders and depression, until now truly subtype-specific compounds are not available, thus limiting the information that is available on the function of individual GABAA receptor subtypes. Here we propose to use a novel combined genetic and pharmacological approach to create a model system (triple point-mutated mice + the non-selective drug diazepam) in which diazepam is a true ?1-specific, ?2-specific, ?3-specific, or ?5-specific full agonist, respectively, enabling the highly selective modulation of the activity of specific GABAA receptor subtypes in order to define the physiological and pharmacological functions of these receptor subtypes, in particular in the regulation of anxiety- and depression-related behaviors. PUBLIC HEALTH RELEVANCE: GABAA receptors are the target structures of clinically used benzodiazepines; however, we have only an incomplete knowledge of the function of individual GABAA receptors subtypes, in large part due to the lack of fully subtype-specific compounds. We are proposing a novel genetic and pharmacological approach to assess the anxiety-reducing and antidepressant-like properties of specific GABAA receptor subtypes. The proposed experiments are expected to clarify the potential role of specific GABAA receptor subtypes as targets for the development of novel antidepressant drugs.

描述（由申请方提供）：GABAA受体是临床使用的苯二氮卓类药物的靶点，可非选择性调节多种GABAA受体亚型。虽然在基于功能丧失方法鉴定GABAa受体亚型的差异功能方面已经取得了一些进展，这开辟了设计用于CNS疾病如焦虑症和抑郁症的新治疗的可能性，但直到现在还没有真正的亚型特异性化合物，因此限制了关于单个GABAa受体亚型功能的可用信息。在这里，我们建议使用一种新的遗传和药理学相结合的方法来创建一个模型系统（三重点突变的小鼠+非选择性药物地西泮），其中地西泮是一个真正的？1、具体？2、具体？3、具体的，还是？5-特异性完全激动剂，从而能够高度选择性地调节特异性GABAa受体亚型的活性，以确定这些受体亚型的生理和药理学功能，特别是在焦虑和抑郁相关行为的调节中。公共卫生相关性：GABAA受体是临床使用的苯二氮卓类药物的靶结构;然而，我们对单个GABAA受体亚型的功能只有不完整的了解，这在很大程度上是由于缺乏完全亚型特异性的化合物。我们提出了一种新的遗传和药理学方法来评估特定GABAA受体亚型的焦虑减轻和抗抑郁样特性。拟议的实验有望阐明特定GABAA受体亚型作为新型抗抑郁药物开发靶点的潜在作用。