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。虽然行为疗法可有效减少MA的使用，但许多入组的患者无法达到显著的禁欲期，这表明需要其他策略。尽管是国家药物滥用研究所（NIDA）的高度优先事项，科学和治疗界也做出了广泛的努力，但尚未确定有效的MA滥用药物。MA作为单胺转运蛋白的底物，被带入神经末梢，通过防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滥用主要归因于其增加突触DA水平的能力。然而，靶向DA系统尚未确定用于管理MA滥用的广泛有效的药物疗法。MA还促进5- HT释放，其介导MA的增强作用。MA滥用的特征还在于DA和5-HT系统的扰动。因此，MA滥用的有效药物可能需要靶向5-HT系统以及DA，这是一种创新策略。丁螺环酮（BUSP）是一种抗焦虑药物，滥用潜力有限，是5-羟色胺5-HT 1A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用于管理阿片样物质和尼古丁使用障碍的有价值的工具，这是由于它们在神经递质紧张度低时刺激受体的能力（即，在禁欲期间）并在神经递质紧张度高时阻断受体（即，在失效之后）。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受体在吸毒动机中起着关键作用。尽管具有良好的药理学特征和积极的临床前结果，但我们不知道任何人体实验室研究测试了BUSP对MA滥用相关作用的影响。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BUSP维持期间MA的阿托伐他汀、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用于管理MA使用障碍的潜在疗效的重要证据。这些结果将有助于拓宽MA药物开发工作的当前临床神经科学范式，而不仅仅关注DA系统。此外，证明市售药物的初步疗效将比等待新分子可用于人体测试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.