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: 8235917
• 负责人: CRAIG R RUSH
• 金额: $ 35.17万
• 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 2013-06-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235917
• 关键词: Admission activity; American; Aminobutyric Acids; Attenuated; Basic Science; Behavior; Behavioral; Central Nervous System Stimulants; Clinical; Cocaine; Dependence; Development; Discrimination; Dopamine; Dose; Drug Kinetics; Educational process of instructing; Epidemiology; Foundations; Goals; Great Lakes Region; Human; Institution; Intelligence; Kentucky; Laboratories; Laboratory Animals; Learning; Location; Maintenance; Measures; Mediating; Methamphetamine; Methamphetamine dependence; Molecular; Nerve; Neurotransmitters; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Placebos; Play; Procedures; Psychostimulant dependence; Public Health; Questionnaires; Relapse; Reporting; Research; Role; Self Administration; Serotonin; Signal Transduction; Stimulus; Synapses; System; Testing; Vesicle; design; dopamine system; drug discrimination; effective therapy; gamma-Aminobutyric Acid; methamphetamine abuse; monoamine; noradrenaline transporter; novel; pre-clinical; preclinical study; prevent; receptor; research study; reuptake; topiramate; volunteer

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.

项目总结/摘要 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- 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，从而减弱对多巴胺的抑制。 被认为是导致其滥用的甲基苯丙胺的行为影响。临床前和人体实验室 实验表明，高效GABAA受体调节剂减弱了行为效应， 在各种行为安排下的兴奋剂。这些结果表明，GABAA受体 调制可能是开发控制甲基苯丙胺滥用药物的一个可行目标。 本申请的首要目标是证明靶向GABAA受体调节是一种可行的方法， 开发药物以控制甲基苯丙胺依赖的战略。这一目标将 这是通过两个“概念验证”实验来实现的，旨在实现两个具体目标。 第一个具体目的是证明GABAA受体调节剂减弱GABAA受体的增强作用。 冰毒为了实现这一目标，我们将确定鼻内给药的增强作用。 使用进行比在高效GABAA受体调节剂维持期间测定甲基苯丙胺 程序（实验1）。兴奋剂的强化作用是其滥用潜力的核心。由此推断， 用于控制兴奋剂依赖性的有效药物疗法将改变药物自我给药。的 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，我们将教志愿者辨别鼻内 甲基苯丙胺使用药物歧视程序（实验2）。一定剂量的甲基苯丙胺 然后在GABAA受体调节剂和安慰剂维持期间进行测试。的区别效果 甲基苯丙胺可能涉及吸毒行为的复发，因为初始剂量（即，失效）可 作为一种区别性刺激信号，发出更多药物的可用性。药物治疗， 甲基苯丙胺的区别刺激效应可能对预防复发有效。 拟议的研究将提供关于靶向GABAA的可行性的初步临床信息。 受体调节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。第一，包容性 药物自我管理和歧视措施，沿着主观效应问卷，将 提供关于强化、区分和主观影响之间关系的信息， 冰毒第二，因为GABAA受体调节剂已被测试为用于治疗糖尿病的药物疗法。 使用类似的行为程序在实验室动物中进行兴奋剂依赖，拟议的研究将 尽管是间接的，但它决定了临床前研究结果推广到人类的程度。投射叙事 甲基苯丙胺依赖是一个重大的公共卫生问题。该研究将提供 关于靶向GABAA受体调节的可行性的重要临床信息 开发药物以控制甲基苯丙胺依赖。