Human methamphetamine self-administration in a progressive-ratio paradigm

渐进比例范例中的人类甲基苯丙胺自我给药

• 批准号: 8032601
• 负责人: Rajkumar Jyotishchandra Sevak
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032601
• 关键词: Accident and Emergency department; Amphetamine Abuse; Amphetamine Dependence; Amphetamines; Attenuated; Behavioral; Cardiovascular system; Clinical Trials; County; Dependence; Dextroamphetamine; Dose; Drug Addiction; Drug abuse; Epidemiology; Evaluation; Experimental Designs; Funding; Health; Human; Impaired cognition; Individual; Infusion procedures; Inpatients; Intravenous; Laboratories; Laboratory Procedures; Los Angeles; Measures; Methamphetamine; Methamphetamine dependence; Methods; Modification; Mus; Outcome; Participant; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebo Effect; Placebos; Procedures; Psychological reinforcement; Public Health; Questionnaires; Research; Rewards; Sampling; Schedule; Screening procedure; Self Administration; Sexually Transmitted Diseases; Signal Transduction; Testing; Visit; Work; capsule; cost; drug of abuse; methamphetamine abuse; novel; reinforcer; response; tool

DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are major public health concerns; however, a widely accepted pharmacotherapy has not yet been identified (Elkashef, 2008). Efforts in this regard have been limited, in part, by the inadequate sensitivity of human laboratory methods for measuring abuse-related behavioral effects (e.g., reinforcing effects) of MA. Enhancing the sensitivity of the human laboratory procedures to reveal sizable reinforcing effects could facilitate the testing of pharmacological agents in modifying these effects. Only a handful of studies have measured the reinforcing effects of MA in the human laboratory, and the procedures used (e.g., choosing between drug and monetary rewards) have yielded only small to moderate effects. The modest reinforcing effects of MA found in these procedures limit the extent to which pharmacological modification can be examined. Notably, progressive-ratio procedure is an efficient method for assessing the reinforcing effects of abused drug. In this procedure, the response requirement (i.e., ratio) for obtaining each reinforcer progressively increases until subjects stop responding. The final ratio completed is the "break point," which reflects the maximum effort expended to receive the reinforcer. Progressive-ratio procedures have not yet been used to study human MA self-administration; and, although d-amphetamine self-administration has been examined using this procedure, the modest effects observed have limited its utility for evaluating pharmacotherapies for amphetamine abuse. Particular experimental design parameters likely contributed to the modest effects found in the d- amphetamine progressive-ratio studies. Notably, in these studies response requirements ranged from either 50 to 6,400 or 25 to 3,200 responses (i.e., mouse clicks) to earn capsules. This contributed to high responses for placebo and low responses for d-amphetamine, resulting in small to moderate magnitudes of the measured reinforcement. We propose to use different response requirements (i.e., 400 to 1,800 clicks) under a progressive-ratio schedule. We hypothesize that the higher "minimal" and lower "maximal" ratios would decrease responding for placebo and increase responding for MA, revealing an enhanced magnitude of the reinforcing effects of MA. Ten MA-dependent individuals will participate in this 11-day inpatient study. They will first sample IV doses of MA (0, 8, 16, and 24 mg), and in subsequent sessions, they will receive opportunities to work for the sampled dose on a progressive-ratio procedure. A battery of subjective-effect questionnaires and cardiovascular measures will be assessed to characterize the effects of MA. We expect that the proposed response requirements will result in low levels of placebo taking and a wide difference between the number of placebo and MA infusions earned, resulting in a large effect size of the MA reinforcement. The proposed research offers to provide a sensitive human laboratory procedure for assessing reinforcing effects of MA. The outcomes could help develop an efficient and economical human laboratory screen of medications for MA dependence. PUBLIC HEALTH RELEVANCE: The application offers to refine a human laboratory procedure, the progressive-ratio schedule, for assessing reinforcing effects of MA in MA-dependent individuals. A widely accepted medication for treating MA dependence is not yet available, and the cost associated with clinical trials is substantial. An efficient human laboratory procedure can, therefore, provide an economical approach for determining preliminary efficacy of medications for MA dependence.

描述（由申请方提供）：甲基苯丙胺（MA）滥用和依赖是主要的公共卫生问题;然而，尚未确定广泛接受的药物治疗（Elkashef，2008）。这方面的努力受到限制，部分原因是用于测量滥用相关行为影响的人类实验室方法灵敏度不足（例如，增强效果）。提高人类实验室程序的敏感性，以揭示相当大的强化作用，可以促进药物的测试，在修改这些影响。只有少数研究在人类实验室中测量了MA的强化效果，以及所使用的程序（例如，在药物和金钱奖励之间进行选择）只产生了小到中等的效果。在这些程序中发现的MA的适度增强作用限制了可以检查药理学修饰的程度。值得注意的是，累进比率程序是评估滥用药物强化作用的有效方法。在此过程中，响应要求（即，比率）逐渐增加，直到受试者停止响应。完成的最终比率是“断点”，它反映了接收该请求所花费的最大努力。进行比程序尚未被用于研究人类MA自我管理，虽然d-苯丙胺自我管理已被检查使用此程序，观察到的适度影响限制了其效用评估药物治疗苯丙胺滥用。特定的实验设计参数可能有助于在d-苯丙胺进行比研究中发现的适度效应。值得注意的是，在这些研究中，响应要求的范围为50至6，400或25至3，200个响应（即，鼠标点击）来获得胶囊。这导致了安慰剂的高响应和d-苯丙胺的低响应，导致了小到中等程度的测量强化。我们建议使用不同的响应要求（即，400到1，800次点击）。我们假设，较高的“最小”和较低的“最大”比率将减少安慰剂的反应，增加MA的反应，揭示了MA的增强效应的增强幅度。10名MA依赖者将参加这项为期11天的住院研究。他们将首先对MA的IV剂量（0，8，16和24 mg）进行采样，在随后的会议中，他们将有机会在累进比例程序中为采样剂量工作。将评估一组主观效应问卷和心血管指标，以表征MA的效应。我们预计，拟定的应答要求将导致安慰剂服用水平较低，安慰剂和MA输注次数之间存在较大差异，从而导致MA强化的效应量较大。拟议的研究提供了一个敏感的人类实验室评估MA的强化效果的程序。这些结果可能有助于开发一种有效和经济的人类实验室药物筛选MA依赖。 公共卫生相关性：该应用程序提供了一个完善的人类实验室程序，渐进比时间表，用于评估MA依赖个体中MA的强化作用。目前还没有一种被广泛接受的治疗MA依赖的药物，与临床试验相关的费用也很高。因此，一个有效的人类实验室程序可以提供一个经济的方法来确定药物对MA依赖的初步疗效。