GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse

描述（由申请人提供）：甲基苯丙胺依赖是一个重大的公共卫生问题。多巴胺在介导甲基苯丙胺的行为效应中起着重要作用。?-氨基丁酸（GABA）系统抑制多巴胺系统。增加GABA活性可能导致对多巴胺系统的更大抑制，从而减弱被认为有助于其滥用的甲基苯丙胺的行为影响。临床前和人体实验室实验已经证明，高效GABAA受体调节剂在各种行为安排下减弱兴奋剂的行为效应。这些研究结果表明，GABAA受体调节可能是一个可行的目标，为药物的发展，以管理甲基苯丙胺滥用。本申请的总体目标是证明靶向GABAA受体调节是开发药物以管理甲基苯丙胺依赖的可行策略。这一目标将通过开展旨在实现两个具体目标的两项“概念验证”实验来实现。 第一个具体目的是证明GABAA受体调节剂减弱甲基苯丙胺的增强作用。为了实现这一目标，我们将使用渐进比率程序确定鼻内甲基苯丙胺在维持期间对高效GABAA受体调节剂的增强作用（Exp. 1）。兴奋剂的强化作用对其滥用潜力至关重要。由此推断，一个有效的药物治疗管理兴奋剂依赖将修改药物自我管理。第二个具体目标是证明GABAA受体调节剂减弱甲基苯丙胺的辨别刺激作用。为了实现这一目标，我们将教导志愿者使用药物辨别程序来辨别鼻内甲基苯丙胺（Exp. 2）。然后，在GABAA受体调节剂和安慰剂维持期间将测试一系列剂量的甲基苯丙胺。甲基苯丙胺的区别作用可能涉及吸毒行为的复发，因为初始剂量（即，失效）可以用作发出更多药物可用性的信号的区别性刺激。减弱甲基苯丙胺的辨别刺激效应的药物疗法可能对预防复发有效。 拟议的研究将提供关于靶向GABAA受体调节的可行性的初步临床信息，用于开发甲基苯丙胺滥用药物。除了临床信息，拟议的研究将提供基础科学和翻译信息。首先，将自我给药和辨别措施与主观效果调查表沿着列入，将提供有关甲基安非他明的强化、辨别和主观效果之间关系的信息。其次，由于GABAA受体调节剂已被测试为使用类似行为程序在实验室动物中治疗兴奋剂依赖的药物疗法，因此拟议的研究将确定（尽管是间接的）临床前研究结果推广到人类的程度。公共卫生相关性：甲基苯丙胺依赖是一个重大的公共卫生问题。拟议的研究将提供有关靶向GABAA受体调节的可行性的重要临床信息，用于开发药物来管理甲基苯丙胺依赖。

DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role in mediating the behavioral effects of methamphetamine. ?-Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratory experiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effects of stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptor modulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viable strategy for the development of medications to manage methamphetamine dependence. This goal will be achieved through the conduct of two "proof-of-concept" experiments designed to accomplish two specific aims. The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects of methamphetamine. To accomplish this aim, we will determine the reinforcing effects of intranasal methamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratio procedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference, then, an effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. The second specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim, we will teach volunteers to discriminate intranasal methamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine will then be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e., a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide initial clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications for methamphetamine abuse. In addition to the clinical information, the proposed research will provide basic-science and translational information. First, the inclusion of drug self-administration and discrimination measures, along with subjective-effect questionnaires, will provide information concerning the relationship between the reinforcing, discriminative and subjective effects of methamphetamine. Second, because GABAA receptor modulators have been tested as pharmacotherapies for stimulant dependence in laboratory animals using similar behavioral procedures, the proposed research will determine, albeit indirectly, the extent those findings from preclinical studies generalize to humans. Public Health Relevance: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications to manage methamphetamine dependence.