Buspirone as a Candidate Medication for Methamphetamine Abuse

丁螺环酮作为甲基苯丙胺滥用的候选药物

• 批准号: 8502027
• 负责人: CRAIG R RUSH
• 金额: $ 20.71万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502027
• 关键词: Abstinence; Admission activity; Adverse effects; Agonist; American; Amphetamines; Anti-Anxiety Agents; Attenuated; Autoreceptors; Behavior Therapy; Behavioral; Benzodiazepines; Buspirone; Cardiovascular system; Cereals; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Communities; Crime; Data; Development; Disease; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Dose; Enrollment; Exploratory/Developmental Grant; Future; Human; Impaired cognition; Laboratories; Laboratory Procedures; Laboratory Research; Locomotion; Maintenance; Mediating; Medical; Methamphetamine; Methamphetamine dependence; Monkeys; Motivation; National Institute of Drug Abuse; Nausea; Nerve; Neurosciences; Neurotransmitters; Nicotine; Nicotine Use Disorder; Norepinephrine; Opioid; Participant; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Physiological; Play; Premature Mortality; Probability; Procedures; Productivity; Public Health; Reporting; Research; Resources; Rodent; Role; Safety; Sedation procedure; Self Administration; Serotonin; Serotonin Receptor 5-HT1A; Synapses; System; Testing; United States; Vesicle; clinical efficacy; clinical practice; cost; dopamine D3 receptor; dopamine system; double-blind placebo controlled trial; drug reinforcement; indexing; innovation; methamphetamine abuse; monoamine; novel; pre-clinical; presynaptic; prevent; public health relevance; receptor; reinforcer; research study; response; stereotypy; success; tool

DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse is an unrelenting public health concern. While behavioral therapies are effective for reducing MA use, many patients enrolled are unable to achieve significant periods of abstinence suggesting other strategies are needed. Despite being a high priority for the National Institute on Drug Abuse (NIDA) and extensive efforts by the scientific and treatment communities, an effective medication for MA abuse has not been identified. MA acts as a substrate for monoamine transporters and is taken into the nerve terminal where it promotes the release of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into the synapse by preventing the accumulation of neurotransmitter in storage vesicles and by carrier-mediated exchange. MA abuse is largely attributed to its ability to increase synaptic DA levels. However, targeting DA systems has not identified a broadly effective pharmacotherapy for managing MA abuse. MA also promotes 5- HT release, which mediates the reinforcing effects of MA. MA abuse is also characterized by perturbations in DA and 5-HT systems. Thus, an effective medication for MA abuse will likely need to target 5-HT systems in addition to DA, which is an innovative strategy. Buspirone (BUSP), an anxiolytic medication with limited abuse potential, is a partial agonist at serotonin 5-HT1A receptors, an antagonist at DA auto receptors, and a selective antagonist at DA D3 receptors. Partial agonists have been recognized as valuable tools for managing opioid and nicotine use disorders due to their ability to stimulate receptors when neurotransmitter tone is low (i.e., during abstinence) and block receptors when neurotransmitter tone is high (i.e., following a lapse). DA auto receptors stabilize dopaminergic tone and antagonists at these receptors can increase DA release. DA D3 receptors play a critical role in motivation to take drugs. Despite a favorable pharmacological profile and positive preclinical results, we are unaware of any human laboratory research that tested the influence of BUSP on the abuse-related effects of MA. Human laboratory research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This proposed study will assess the reinforcin, subject-rated, performance, and physiological effects of MA during maintenance on BUSP. Human drug reinforcement procedures have good predictive validity for the clinical efficacy of MA pharmacotherapies. By determining how BUSP impacts the behavioral effects of MA, we will provide important evidence regarding the potential efficacy of this compound for managing MA use disorders. These results will help to broaden the current clinical neuroscience paradigm of MA medications development efforts beyond a focus on DA systems. In addition, demonstrating the initial efficacy of a commercially available drug will impact clinical research more quickly than waiting for novel molecules to be available for testing in humans.

描述(申请人提供)：滥用甲基苯丙胺(MA)是一个无情的公共卫生问题。虽然行为疗法在减少MA使用方面是有效的，但许多纳入研究的患者无法实现显著的戒断期，这表明还需要其他策略。尽管是国家药物滥用研究所(NIDA)的高度优先事项以及科学界和治疗界的广泛努力，但尚未确定治疗MA滥用的有效药物。MA作为单胺转运体的底物，被带到神经末梢，通过阻止神经递质在储存囊中的积累和载体介导的交换，促进多巴胺(DA)、5-羟色胺(5-HT)和去甲肾上腺素(NE)释放到突触中。MA的滥用在很大程度上归因于其增加突触DA水平的能力。然而，针对DA系统还没有确定一种广泛有效的药物疗法来管理MA滥用。MA还促进5-羟色胺的释放，5-羟色胺的释放介导MA的强化作用。MA滥用的特征还表现为DA和5-羟色胺系统的扰动。因此，治疗MA滥用的有效药物可能需要针对DA以外的5-羟色胺系统，这是一种创新的策略。丁螺环酮(BUSP)是一种滥用潜力有限的抗焦虑药物，是5-羟色胺5-HT1a受体的部分激动剂、DA自身受体的拮抗剂和DA D3受体的选择性拮抗剂。部分激动剂被认为是管理阿片和尼古丁使用障碍的有价值的工具，因为它们能够在神经递质张力低时(即戒断期间)刺激受体，并在神经递质张力高时(即在失误后)阻断受体。DA自身受体稳定多巴胺能张力，这些受体上的拮抗剂可以增加DA的释放。DA D3受体在吸毒动机中起着关键作用。尽管有良好的药理学特征和积极的临床前结果，我们还不知道有任何人体实验室研究测试了BUSP对MA滥用相关效应的影响。人体实验室研究可以在进行大规模临床试验之前有效地筛选潜在的药物。这项拟议的研究将评估MA在BUSP维护期间的增援、受试者评级、性能和生理影响。人类药物强化程序对MA药物治疗的临床疗效具有良好的预测有效性。通过确定BUSP如何影响MA的行为影响，我们将为该化合物在管理MA使用障碍方面的潜在疗效提供重要证据。这些结果将有助于拓宽目前临床神经科学的MA药物开发努力的范式，超越对DA系统的关注。此外，与等待新分子用于人体试验相比，展示商业化药物的初步疗效将更快地影响临床研究。