GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse

GABAA 调节作为开发甲基苯丙胺滥用药物的目标

• 批准号: 7563346
• 负责人: CRAIG R RUSH
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563346
• 关键词: Admission activity; American; Aminobutyric Acid; Aminobutyric Acids; Attenuated; Basic Science; Behavior; Behavioral; Central Nervous System Stimulants; Chromosome Pairing; Clinical; Cocaine; Dependence; Development; Discrimination; Dopamine; Dose; Drug Kinetics; Educational process of instructing; Elevation; Foundations; Goals; Great Lakes Region; Human; Institution; Intelligence; Kentucky; Laboratories; Laboratory Animals; Learning; Location; Maintenance; Measures; Mediating; Methamphetamine; Molecular; Nerve; Neurotransmitters; Numbers; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Placebos; Play; Procedures; Psychostimulant dependence; Public Health; Questionnaires; Range; Relapse; Reporting; Research; Role; Self Administration; Serotonin; Signal Transduction; Stimulus; Synapses; System; Testing; Thinking; Vesicle; concept; design; dopamine system; drug discrimination; gamma-Aminobutyric Acid; monoamine; noradrenaline transporter; novel; pre-clinical; preclinical study; prevent; receptor; research study; reuptake; topiramate; volunteer

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.

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。多巴胺在调节甲基苯丙胺的行为效应中发挥着重要作用。 γ-氨基丁酸（GABA）系统抑制多巴胺系统。 GABA 活性的增加可能会导致多巴胺系统受到更大的抑制，从而减弱甲基苯丙胺的行为影响，而甲基苯丙胺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表明，高效 GABAA 受体调节剂可减弱多种行为安排下兴奋剂的行为效应。这些发现表明，GABAA 受体调节可能是开发治疗甲基苯丙胺滥用药物的可行目标。该应用的总体目标是证明靶向 GABAA 受体调节是开发治疗甲基苯丙胺依赖药物的可行策略。这一目标将通过进行两项旨在实现两个特定目标的“概念验证”实验来实现。 第一个具体目标是证明 GABAA 受体调节剂可以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 受体调节剂期间的增强作用（实验 1）。兴奋剂的增强作用是其滥用可能性的核心。由此推断，管理兴奋剂依赖的有效药物疗法将改变药物的自我给药。第二个具体目标是证明 GABAA 受体调节剂可以减弱甲基苯丙胺的辨别刺激作用。为了实现这一目标，我们将教志愿者使用药物辨别程序来辨别鼻内甲基苯丙胺（实验 2）。然后，在维持 GABAA 受体调节剂和安慰剂的过程中，将测试一系列剂量的甲基苯丙胺。甲基苯丙胺的辨别作用可能与吸毒行为的复发有关，因为初始剂量（即失效）可能起到辨别刺激的作用，发出更多药物可用性的信号。减弱甲基苯丙胺的歧视性刺激作用的药物疗法可能有效预防复发。 拟议的研究将提供有关针对 GABAA 受体调节的可行性的初步临床信息，以开发治疗甲基苯丙胺滥用的药物。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歧视措施，以及主观效果问卷，将提供有关甲基苯丙胺的强化、歧视和主观效果之间关系的信息。其次，由于 GABAA 受体调节剂已在实验动物中使用类似的行为程序进行了兴奋剂依赖性药物疗法的测试，因此拟议的研究将确定（尽管是间接的）临床前研究的这些发现在多大程度上推广到人类。公共卫生相关性：甲基苯丙胺依赖是一个重要的公共卫生问题。拟议的研究将提供有关针对 GABAA 受体调节的可行性的重要临床信息，以开发治疗甲基苯丙胺依赖的药物。