Mechanisms of Carisoprodol Abuse

描述（由申请方提供）：卡立普多（索马（R））是一种中枢作用的骨骼肌松弛剂，常用于治疗急性肌肉骨骼疾病。近年来，人们越来越关注卡立普多作为滥用药物的可能性。1991年，卡立普多在234种有滥用潜力的药物中排名第54位。仅仅八年后，药物滥用警告网络将卡立普多确定为第14大滥用药物，排名高于羟考酮，美沙酮和LSD。为了支持这一点，最近的报告证实了卡立普多滥用所涉及的危险，包括导致癫痫发作和死亡的严重戒断。然而，其作用机制仍不清楚。直到最近，人们普遍认为卡立普多的镇静作用主要是由于其代谢产物甲丙氨酯。然而，在我们实验室进行的初步体内和体外研究表明，卡立普多本身具有活性，其作用似乎是通过GABAA受体（GABAAR）（哺乳动物大脑中的主要抑制性神经递质受体）的新型调节介导的。这可能是卡立普多增强CNS抑制剂镇静作用的能力的基础，从而导致其滥用的可能性。事实上，对卡立普多滥用增加的担忧导致缉毒局联系国家药物滥用研究所，以协助确定卡立普多的滥用责任。基于我们的初步研究结果，我们假设卡立普多本身会引起CNS抑制作用，并且这些作用通过与GABAA受体的新型相互作用介导。拟议研究的总体目标是在行为和分子水平上确定介导卡立普多滥用的机制。我们将在体内同时利用（药物鉴别和中毒、耐受性和戒断观察以及药代动力学分析）和体外（卡立普多对重组GABAA受体的特定构型的评估）方法来解决以下特定目的：1）表征卡立普多的区别性刺激作用; 2）研究卡立普多是否在体内自身产生作用或需要代谢为甲丙氨酯; 3）评估卡立普多依赖的程度和戒断的严重程度; 4）鉴定对卡立普多的变构调节和直接门控作用至关重要的GABAa受体亚基;和5）鉴定赋予卡立普多敏感性的GABAa受体亚基结构域。鉴于卡立普多滥用造成的现有和潜在危险，确定这种药物的作用机制至关重要。我们提出的研究将大大增加我们对卡立普多作为治疗药物和滥用药物的作用机制的理解。这些知识可以为治疗卡立普多依赖和戒断提供见解。公共卫生相关性：肌肉松弛剂Carisoprodol（索马（R））正以惊人的速度被滥用;停止过度使用这种药物会导致癫痫发作甚至死亡。迫切需要开发能够治疗这些症状的新药，以及不太可能被滥用的新药。拟议的研究将提供解决这两个目前未满足的医疗需求所需的基本信息。

DESCRIPTION (provided by applicant): Carisoprodol (Soma(R)) is a centrally-acting skeletal muscle relaxant frequently prescribed for the treatment of acute musculoskeletal conditions. In recent years, there has been increasing concern regarding carisoprodol's potential as a drug of abuse. In 1991, carisoprodol was ranked 54th among 234 drugs with abuse potential. Only eight years later, the Drug Abuse Warning Network identified carisoprodol as the 14th most abused drug, ranking higher than oxycodone, methadone, and LSD. In support of this, recent reports have substantiated the dangers involved in carisoprodol abuse, including severe withdrawal leading to seizures and death. However, its mechanism of action remains unclear. Until recently, it was widely accepted that the sedative effects of carisoprodol were predominantly due to its metabolite, meprobamate. However, preliminary in vivo and in vitro studies conducted in our laboratory demonstrate that carisoprodol itself is active, and its actions appear to be mediated via novel modulation of the GABAA receptor (GABAAR), the predominant inhibitory neurotransmitter receptor in mammalian brain. This may underlie the capacity of carisoprodol to enhance the sedative effects of CNS depressants, contributing to its potential for abuse. Indeed, concerns about the rise in abuse of carisoprodol have led the Drug Enforcement Agency to contact the National Institute on Drug Abuse for assistance in determining the abuse liability of carisoprodol. Based on our preliminary findings, we hypothesize that carisoprodol itself causes depressive CNS effects, and that these actions are mediated via a novel interaction with the GABAA receptor. The overall goal of the proposed study is to identify the mechanisms that mediate carisoprodol abuse, at both the behavioral and molecular level. We will utilize both in vivo (drug discrimination and observation of intoxication, tolerance and withdrawal, and pharmacokinetic analysis) and in vitro (assessment of carisoprodol on specific configurations of recombinant GABAA receptors) approaches to address the following specific aims: 1) To characterize the discriminative stimulus effects of carisoprodol; 2) To investigate whether carisoprodol produces effects on its own in vivo or requires being metabolized to meprobamate; 3) To assess the extent of carisoprodol dependence and severity of withdrawal; 4) To identify GABAA receptor subunits critical for allosteric modulatory and direct gating effects of carisoprodol; and 5) To identify GABAA receptor subunit domains that confer carisoprodol sensitivity. Given the present and potential dangers posed by carisoprodol abuse, it is of crucial importance to determine the mechanism of action of this drug. Our proposed studies will substantially increase our understanding of the mechanism of action of carisoprodol as a therapeutic agent and as a drug of abuse. This knowledge may provide insight into treating carisoprodol dependence, and withdrawal. PUBLIC HEALTH RELEVANCE: The muscle relaxant Carisoprodol (Soma(R)) is being abused increasingly at an alarming rate; withdrawal from overuse of this drug can cause seizures and even death. There is an urgent need to develop new drugs that can treat these symptoms, as well as new drugs that are less likely to be abused. The proposed studies will provide the fundamental information needed to address both of these current unmet medical needs.