Studies on the role of GABA in Cocaine Addiction

描述(由申请人提供)：拟议研究的目标是 研究主要抑制性神经转运蛋白的作用 伽马氨基丁酸(GABA)在强化刺激和辨别刺激中的作用 可卡因的影响。了解潜在的神经生物学机制 可卡因的行为效应对发展有效的 治疗可卡因成瘾的药物。涉及的主要机制是 可卡因的增强作用是激活中脑边缘多巴胺 系统。最近的研究表明，GABA对中脑边缘的调节作用 DA活性，以及促进GABA能神经传递的药物 可以改变可卡因对人类和人类的某些行为影响 实验动物。拟议的研究将评估 GABA对自我给药、恢复和保护的药理学调节作用 区分低剂量和高剂量可卡因。GABA能神经传递 可以通过多种不同的机制(即，激活或 阻断GABAA和GABAB受体，抑制GABA转氨酶， 抑制GABA合成和抑制GABA重摄取)；药物影响 这些机制中的每一个都将使用几个程序进行评估，以提供 GABA能对小鼠行为效应影响的综合评价 可能与成瘾有关的可卡因。药物自我给药和 恢复动物寻药提供有效的药物信息 分别是强化和复发。中国的药物歧视程序 动物提供的信息类似于对主观影响的评估 人类，并提供了一种高度选择性的行为测量，通常 与药物在特定神经递质系统的活性相对应。一 目的是调查GABA能药物是否改变正在进行的 可卡因自我管理。第二个目标是探索GABA能药物 改变以最大工作量衡量的吸食可卡因的动机 在可卡因注射的累进比率时间表下。任何事物的专一性 服用可卡因的效果将与一种非药物进行平行研究 使用与自我管理和渐进式相同的程序的增强剂 比率第三个目标将确定GABA能药物是否会改变“启动” 可卡因对恢复自我管理的影响(即， 寻找毒品)。第四个目标是评估GABA能药物是否会改变 可卡因的辨别性刺激效应。这些研究的结果将 增加我们对GABA在行为效应中的作用的理解 可卡因，并可能导致更好的治疗药物的开发 可卡因成瘾。

DESCRIPTION (provided by applicant): The goal of the proposed research is to investigate the role of the major inhibitory neurotransrnitter gammaaminobutyric acid (GABA) in the reinforcing and discriminative stimulus effects of cocaine. Understanding the neurobiological mechanisms underlying the behavioral effects of cocaine are critical for the development of effective medications for cocaine addiction. The primary mechanism involved in the reinforcing effects of cocaine is activation of the mesolimbic dopamine (DA) system. Recent studies have indicated a modulatory role of GABA on mesolimbic DA activity, and drugs that facilitate GABAergic neurotransmission have been shown to alter some of the behavioral effects of cocaine in both humans and laboratory animals. The proposed studies will evaluate the effects of pharmacoiogical modulation of GABA on self-administration, reinstatement and discrimination of low and high doses of cocaine. GABAergic neurotransmission can be altered by a number of different mechanisms (i.e., activation or blockade of GABAA and GABAB receptors, inhibition of GABA transaminase, inhibition of GABA synthesis and inhibition of GABA reuptake); drugs affecting each of these mechanisms will be evaluated using several procedures to provide a comprehensive assessment of GABAergic influence on the behavioral effects of cocaine which may be relevant to addiction. Drug self-administration and reinstatement of drug-seeking in animals provide valid information on drug reinforcement and relapse, respectively. Drug discrimination procedures in animals provide information analogous to assessment of subjective effects in humans, and provide a highly selective behavioral measure which often corresponds with a drug's activity at a specific neurotransmitter system. One aim is to investigate if GABAergic drugs alter the rate and pattern of ongoing cocaine self-administration. A second aim is to explore if GABAergic drugs alter the motivation to take cocaine as measured by the maximum work output under a progressive ratio schedule of cocaine injection. The specificity of any effect on cocaine-taking will be evaluated in parallel studies with a non-drug reinforcer using the same procedures as for self-administration and progressive ratio. A third aim will determine if GABAergic drugs alter the 'priming' effects of cocaine on reinstatement of self-administration (i.e., drug-seeking). A fourth aim is to evaluate if GABAergic drugs alter the discriminative stimulus effects of cocaine. The results of these studies will increase our understanding of the role of GABA in the behavioral effects of cocaine and may lead to the development of better medications for the treatment of cocaine addiction.