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: 8650812
• 负责人: CRAIG R RUSH
• 金额: $ 16.72万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650812
• 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（由申请人提供）：甲基苯丙胺 (MA) 滥用是一个持续不断的公共卫生问题。虽然行为疗法可有效减少 MA 的使用，但许多入组患者无法实现显着的禁欲期，这表明需要其他策略。尽管这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，但尚未找到治疗 MA 滥用的有效药物。 MA 作为单胺转运蛋白的底物，被摄入神经末梢，通过阻止神经递质在储存囊泡中的积累和载体介导的交换，促进多巴胺 (DA)、血清素 (5-HT) 和去甲肾上腺素 (NE) 释放到突触中。 MA 滥用很大程度上归因于其增加突触 DA 水平的能力。然而，针对 DA 系统尚未确定一种广泛有效的药物疗法来管理 MA 滥用。 MA 还促进 5-HT 释放，从而介导 MA 的增强作用。 MA 滥用的另一个特点是 DA 和 5-HT 系统的扰动。因此，针对 MA 滥用的有效药物可能需要除 DA 之外还针对 5-HT 系统，这是一种创新策略。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。部分激动剂已被认为是治疗阿片类药物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较低时（即禁欲期间）刺激受体，并在神经递质张力较高时（即戒烟后）阻断受体。 DA自身受体稳定多巴胺能张力，这些受体的拮抗剂可以增加DA释放。 DA D3 受体在吸毒动机中发挥着关键作用。尽管具有良好的药理学特征和积极的临床前结果，但我们不知道有任何人体实验室研究测试了 BUSP 对 MA 滥用相关影响的影响。人体实验室研究可以在进行大规模临床试验之前有效筛选潜在的药物。这项拟议的研究将评估维持 BUSP 期间 MA 的强化、受试者评分、表现和生理影响。人体药物强化程序对 MA 药物疗法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 的行为效应，我们将提供有关该化合物治疗 MA 使用障碍的潜在功效的重要证据。这些结果将有助于拓宽当前 MA 药物开发工作的临床神经科学范式，超越对 DA 系统的关注。此外，证明市售药物的初步疗效将比等待新分子用于人体测试更快地影响临床研究。