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The Role of GABA A Receptor Subtypes in Benzodiazepine Abuse Liability

GABA A 受体亚型在苯二氮卓滥用倾向中的作用

基本信息

批准号：
8543694
负责人：
Uwe Rudolph
金额：
$ 7.58万
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：
2012-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8543694
关键词：
Adverse effects Affect Agonist Anxiety Anxiety Disorders Arginine Behavior Behavioral Benzodiazepines Biological Models Brain Cells Chemicals Chemosensitization Clinical Cognitive deficits Dementia Dependence Development Diazepam Future GABA Agents GABA-A Receptor Genetic Histidine Impaired cognition Individual Knock-in Mouse Knowledge Midazolam Molecular Target Moods Motivation Mus Mutant Strains Mice Mutate Neurons Nucleus Accumbens Oral Pharmaceutical Preparations Point Mutation Process Property Rattus Regulation Reporting Rewards Role Schizophrenia Self Administration Self Stimulation Signal Transduction Sleeplessness System Testing Ventral Tegmental Area Work base cell type chronic pain dopaminergic neuron drug development drug of abuse hippocampal pyramidal neuron in vivo neurobiological mechanism novel prescription drug abuse receptor response zolpidem

项目摘要

DESCRIPTION (provided by applicant): Benzodiazepines are among the most widely abused drugs, and like other drugs of abuse, they "hijack" the brain's dopaminergic reward system, in which several GABAA receptor subtypes are expressed in different neuronal cell types. The modulation of the reward system and of benzodiazepine self-administration by distinct GABAA receptor subtypes is only poorly understood. Here, we want to test the hypothesis that GABAA receptors bidirectionally modulate these behaviors. In the absence of chemical compounds which are truly specific for a GABAA receptor subtype, we propose to use a novel combined genetic and pharmacological approach to create a model system which will enable highly specific modulation of the activity of individual GABAA receptor subtypes. This will be achieved by using the non- selective benzodiazepine drugs diazepam and midazolam in triple point-mutated mice, in which these drugs are a true ?1-specific, ? 2-specific, ? 3-specific, or ? 5-specific full agonists, respectively. This system will make it possible to test whether potentiatio of a particular GABAA receptor subtype is sufficient for reward enhancement and benzodiazepine self-administration.

描述（由申请人提供）：苯二氮卓类药物是滥用最广泛的药物之一，与其他滥用药物一样，它们“劫持”了大脑的多巴胺能奖励系统，其中几种GABAA受体亚型在不同的神经细胞类型中表达。不同GABAA受体亚型对奖励系统和苯二氮卓类药物自我给药的调节知之甚少。在这里，我们想要验证GABAA受体双向调节这些行为的假设。在缺乏真正特异性GABAA受体亚型的化合物的情况下，我们建议使用一种新的结合遗传和药理学的方法来创建一个模型系统，该模型系统将能够高度特异性地调节单个GABAA受体亚型的活性。这将通过在三点突变小鼠中使用非选择性苯二氮卓类药物地西泮和咪达唑仑来实现，其中这些药物是真正的？这个例子,?2-specific, ?3特异性的，还是？5种特异性的完全激动剂。该系统将有可能测试特定GABAA受体亚型的增强是否足以增强奖励和苯二氮卓类药物的自我给药。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia.

DOI：
10.1016/j.neuropharm.2016.07.004
发表时间：
2016-10
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Ralvenius WT;Acuña MA;Benke D;Matthey A;Daali Y;Rudolph U;Desmeules J;Zeilhofer HU;Besson M
通讯作者：
Besson M

Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype.