Buspirone as a Candidate Medication for Methamphetamine Abuse

描述（由申请人提供）：甲基苯丙胺（MA）滥用是一个无情的公共卫生问题。虽然行为疗法对减少MA的使用是有效的，但许多入组的患者无法达到显著的戒断期，这表明需要其他策略。尽管美国国家药物滥用研究所（NIDA）高度重视这一问题，科学界和治疗界也做出了广泛的努力，但尚未找到一种有效的治疗MA滥用的药物。MA作为单胺转运体的底物，被带入神经末梢，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）向突触的释放。MA滥用很大程度上归因于其增加突触DA水平的能力。然而，靶向DA系统尚未确定一种广泛有效的药物治疗来管理MA滥用。MA还促进5- HT的释放，从而介导MA的强化作用。MA滥用还表现为DA和5-羟色胺系统的扰动。因此，除了DA之外，MA滥用的有效药物可能还需要针对5-HT系统，这是一种创新策略。丁螺环酮（BUSP）是一种具有有限滥用潜力的抗焦虑药物，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管理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低（即，在戒断期间）时刺激受体，并在神经递质张力高（即，在失效后）时阻断受体。DA自身受体稳定多巴胺能张力，这些受体的拮抗剂可增加DA的释放。DA D3受体在药物服用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，但我们不知道有任何人体实验室研究测试了BUSP对MA滥用相关效应的影响。在进行大规模临床试验之前，人体实验室研究可以有效地筛选潜在的药物。这项拟议的研究将评估在BUSP维持期间MA的强化，受试者评分，性能和生理效应。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效度。通过确定BUSP如何影响MA的行为效应，我们将为该化合物治疗MA使用障碍的潜在功效提供重要证据。这些结果将有助于拓宽目前MA药物开发的临床神经科学范式，使其不再局限于DA系统。此外，证明一种市售药物的初步疗效将比等待新分子可用于人体试验更快地影响临床研究。

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.