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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：
8278153
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：
2012-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278153
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. PUBLIC HEALTH RELEVANCE: The neurobiological mechanisms underlying benzodiazepine abuse are not well understood, and in particular, the roles of the individual GABAA receptor subtypes in reward-related and self-administration behaviors are largely unknown. We propose to examine whether any of the major four benzodiazepine- sensitive GABAA receptor subtypes is sufficient for modulation of these behavioral responses and plan to demonstrate that GABAA receptors bidirectionally modulate these processes. The knowledge of how each of these GABAA receptor subtypes affects the abuse potential of benzodiazepines is relevant for the development of GABAA receptor subtype-selective compounds for the treatment of anxiety, chronic pain, cognitive deficits, and of benzodiazepine abuse.

描述(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”大脑的多巴胺能奖赏系统，在该系统中，几种GABAA受体亚型在不同的神经细胞类型中表达。不同的GABAA受体亚型对奖赏系统和苯二氮卓类药物自身给药的调节作用还知之甚少。在这里，我们想测试GABAA受体双向调节这些行为的假设。在缺乏真正针对GABAA受体亚型的化合物的情况下，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，该模型系统将能够对单个GABAA受体亚型的活性进行高度特异性的调节。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安定和咪达唑仑来实现，在这些药物中，这些药物分别是真正的1特异性、2特异性、3特异性或5特异性的完全激动剂。该系统将使测试特定GABAA受体亚型的增强是否足以增强奖赏和苯二氮卓类药物的自我给药成为可能。公共卫生相关性：苯二氮类药物滥用的神经生物学机制尚不清楚，尤其是单个GABAA受体亚型在奖赏相关和自我给药行为中的作用在很大程度上是未知的。我们建议检查四种主要的苯二氮卓类敏感的GABAA受体亚型中是否有任何一种足以调节这些行为反应，并计划证明GABAA受体双向调节这些过程。了解这些GABAA受体亚型中的每一种如何影响苯二氮类药物的滥用潜力，对于开发GABAA受体亚型选择性化合物治疗焦虑、慢性疼痛、认知缺陷和苯二氮类药物滥用具有重要意义。