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。GABA活性的增加可能导致对多巴胺系统的更大抑制，从而减弱甲基苯丙胺的行为影响，这被认为是导致其滥用的原因。临床前和人体实验室实验表明，高效的GABAA受体调节剂在各种行为安排下减弱兴奋剂的行为效应。这些发现表明，GABAA受体调节可能是开发控制甲基苯丙胺滥用药物的可行靶点。本应用程序的总体目标是证明靶向GABAA受体调节是一种可行的策略，用于开发药物来管理甲基苯丙胺依赖。这一目标将通过进行两个“概念验证”实验来实现，旨在实现两个具体目标。第一个具体目标是证明GABAA受体调节剂减弱甲基苯丙胺的强化作用。为了实现这一目标，我们将使用递进比例程序确定鼻内甲基苯丙胺在维持高效GABAA受体调节剂期间的强化作用（实验1）。兴奋剂的强化作用是其滥用潜力的核心。由此推断，控制兴奋剂依赖的有效药物疗法将改变药物自我给药。第二个具体目标是证明GABAA受体调节剂减弱甲基苯丙胺的鉴别刺激效应。为了实现这一目标，我们将教志愿者使用药物鉴别程序来辨别鼻内甲基苯丙胺（实验2）。在维持期间，甲基苯丙胺的剂量范围将在GABAA受体调节剂和安慰剂上进行测试。甲基苯丙胺的区别性作用可能与吸毒行为的复发有关，因为初始剂量（即失效）可能起到区别性刺激的作用，表明可以获得更多的毒品。减轻甲基苯丙胺的鉴别刺激作用的药物治疗可能对预防复发有效。拟议的研究将提供关于靶向GABAA受体调节甲基苯丙胺滥用药物开发可行性的初步临床信息。除了临床信息外，拟议的研究还将提供基础科学和转化信息。首先，纳入药物自我给药和甄别措施以及主观效果调查表，将提供有关甲基苯丙胺强化、甄别和主观效果之间关系的资料。其次，由于GABAA受体调节剂已经在实验动物中使用类似的行为程序作为兴奋剂依赖的药物疗法进行了测试，因此拟议的研究将确定（尽管是间接地）临床前研究的结果在多大程度上适用于人类。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。拟议的研究将为靶向GABAA受体调节的可行性提供重要的临床信息，以开发治疗甲基苯丙胺依赖的药物。

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.