Mechanisms of Carisoprodol Abuse

描述(由申请人提供)：卡利索前列醇(SOMA(R))是一种中枢作用的骨骼肌松弛剂，经常用于治疗急性肌肉骨骼疾病。近年来，人们越来越关注卡里索前列醇作为一种滥用药物的潜力。1991年，卡利索前列醇在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利索前列醇列为滥用最多的药物第14位，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里索前列醇滥用所涉及的危险，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，人们普遍认为卡利索前列醇的镇静作用主要是由于它的代谢物甲丙氨酸酯。然而，我们实验室在体内和体外进行的初步研究表明，卡利索前列醇本身是有效的，其作用似乎是通过对哺乳动物大脑中主要的抑制性神经递质受体GABAA受体(GABAAR)的新的调节来实现的。这可能是卡利索前列醇增强中枢神经系统抑制剂的镇静作用的基础，从而增加了其滥用的可能性。事实上，对卡里索前列醇滥用增加的担忧已导致禁毒署与国家药物滥用研究所联系，以协助确定卡里索前列醇的滥用责任。根据我们的初步发现，我们假设卡利索前列醇本身引起了抑郁的中枢神经系统效应，并且这些作用是通过与GABAA受体的一种新的相互作用来介导的。这项拟议研究的总体目标是在行为和分子水平上确定调节卡利索前列醇滥用的机制。我们将利用体内(药物鉴别和中毒观察、耐受性和戒断以及药代动力学分析)和体外(评估卡利索前列醇对重组GABAA受体特定配置的评估)方法来解决下列特定目标：1)表征卡利索前列醇的区分性刺激效应；2)研究卡利索前列醇是否在体内自行产生作用或需要被代谢为甲丙氨酸酯；3)评估卡利索前列醇的依赖程度和戒断严重程度；4)确定对卡索前列醇的变构调节和直接门控作用至关重要的GABAA受体亚单位；以及5)确定导致卡索前列醇敏感性的GABAA受体亚单位。鉴于卡利索前列醇滥用目前和潜在的危险，确定该药物的作用机制至关重要。我们建议的研究将大大增加我们对卡利索前列醇作为治疗剂和滥用药物的作用机制的理解。这些知识可能为治疗卡利索前列醇依赖和戒断提供洞察力。与公共健康相关：肌肉松弛剂卡利索前列醇(SOMA(R))正以惊人的速度被滥用；停止过度使用这种药物可能会导致癫痫发作，甚至死亡。目前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当前未得到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.