GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse

项目摘要/摘要 对甲基苯丙胺的依赖是一个重大的公共卫生问题。多巴胺在人体内起着重要作用 调节甲基苯丙胺的行为效应。-氨基丁酸(GABA)系统抑制多巴胺 系统。增加GABA活性可能会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被认为是导致其滥用的原因之一。临床前和人体实验室 实验证明，高效的GABAA受体调节剂可以减弱行为效应 在各种行为安排下的兴奋剂。这些发现表明GABAA受体 调制可能是开发药物来管理甲基苯丙胺滥用的可行目标。 本申请的主要目标是证明靶向GABAA受体调节是可行的 开发药物以控制甲基苯丙胺依赖的战略。这个目标将是 通过开展两个旨在实现两个具体目标的“概念验证”实验来实现这一目标。 第一个具体目的是证明GABAA受体调节剂减弱 冰毒。为了实现这一目标，我们将确定鼻腔内注射的强化效果。 甲基苯丙胺维持高效GABAA受体调节剂的累进比率 程序(经验1)。兴奋剂的强化作用是其滥用潜力的核心。由此推论， 控制兴奋剂依赖的有效药物疗法将改善药物自我给药。这个 第二个具体目的是证明GABAA受体调节剂减弱辨别性刺激 甲基苯丙胺的影响。为了实现这一目标，我们将教志愿者如何辨别鼻腔 使用毒品识别程序的甲基苯丙胺(Exp.2)。一系列剂量的甲基苯丙胺将 然后在维护期间接受GABAA受体调节剂和安慰剂的测试。的区别性效应 甲基苯丙胺可能与复吸吸毒行为有关，因为最初的剂量(即失效)可能 起到歧视性刺激的作用，表明有更多的药物可用。瘦身的药物疗法 甲基苯丙胺的辨别刺激作用可能是预防复发的有效方法。 拟议的研究将提供有关靶向GABAA的可行性的初步临床信息 开发治疗甲基苯丙胺滥用药物的受体调节。除了临床上的 信息方面，拟议的研究将提供基础科学和翻译信息。第一，纳入 药物自我管理和歧视措施，以及主观效果问卷，将 提供有关加强、区别和主观影响之间的关系的信息 冰毒。其次，因为GABAA受体调节剂已经被测试为治疗 使用类似的行为程序对实验室动物进行兴奋剂依赖，拟议的研究将 确定，尽管是间接的，临床前研究的结果在多大程度上适用于人类。投射叙事 对甲基苯丙胺的依赖是一个重大的公共卫生问题。拟议的研究将提供 关于靶向GABAA受体调节对血管内皮细胞生长的可行性的重要临床信息 开发治疗甲基苯丙胺依赖的药物。

PROJECT SUMMARY/ABTRACT 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 that findings from preclinical studies generalize to humans. PROJECTIVE NARRATIVE 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.