A Human Laboratory Study to Investigate Buspirone for Cocaine Use Disorders

描述（由申请人提供）：可卡因使用障碍是一个无情的公共卫生问题。深入的研究工作已经产生了减少可卡因使用的行为干预措施，然而，这些干预措施并不是普遍有效的，治疗效果会随着时间的推移而减弱。开发一种提高这些干预措施效力的药物疗法是国家药物滥用研究所的一项优先事项。在中枢神经系统中，可卡因阻断了多巴胺和血清素的再摄取并诱导其释放，因此，成功的可卡因药物治疗可能需要针对这两种神经递质。丁螺环酮是一种具有有限滥用潜力的抗焦虑药物，是多巴胺自身受体的拮抗剂和血清素5- HT1A受体的部分激动剂；这两种受体在可卡因滥用相关效应中都起着至关重要的作用。多巴胺自受体稳定多巴胺能张力，这些受体的拮抗剂可以增加多巴胺的释放。此外，具有部分激动剂活性的药物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。虽然丁螺环酮产生的药理作用可能对治疗可卡因依赖有益，但我们不知道有任何人体实验室研究测试了丁螺环酮对可卡因行为效应的影响，这是一个值得注意的文献空白，因为此类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。本研究将评估可卡因在丁螺环酮维持期间的强化、受试者评定、认知、表现和生理效应。通过确定丁螺环酮如何影响可卡因的行为效应，我们将为这种化合物治疗可卡因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的临床神经科学范式，使可卡因药物的开发工作超越对多巴胺系统的关注。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): Cocaine use disorders are an unrelenting public health concern. Intensive research efforts have yielded behavioral interventions that reduce cocaine use, however, these interventions are not universally effective and treatment effects diminish over time. Development of a pharmacotherapy that enhances the efficacy of these interventions is a priority for the National Institute on Drug Abuse. In the central nervous system cocaine blocks the reuptake and induces release of dopamine and serotonin, thus a successful cocaine pharmacotherapy will likely need to target both of those neurotransmitters. Buspirone, an anxiolytic medication with limited abuse potential, is an antagonist at dopamine autoreceptors and a partial agonist at serotonin 5- HT1A receptors; both of these receptors play crucial roles in the abuse-related effects of cocaine. Dopamine autoreceptors stabilize dopaminergic tone and antagonists at these receptors can increase dopamine release. Moreover, medications with partial agonist activity 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). Although buspirone produces pharmacological effects that are likely beneficial for treating cocaine dependence, we are unaware of any human laboratory research that has tested the influence of buspirone on the behavioral effects of cocaine, a notable gap in the literature considering that such research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This study will assess the reinforcing, subject- rated, cognitive, performance and physiological effects of cocaine during maintenance on buspirone. By determining how buspirone impacts the behavioral effects of cocaine, we will provide important evidence regarding the potential efficacy of this compound for managing cocaine use disorders. These results will help to broaden the current clinical neuroscience paradigm of cocaine medications development efforts beyond a focus on dopamine 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. PUBLIC HEALTH RELEVANCE: A successful pharmacological adjunct for managing cocaine use disorders will likely need to target more than the dopamine system. Buspirone, an anxiolytic with limited abuse potential, is a serotonin 5HT1A receptor partial agonist and dopamine autoreceptor antagonist that may be effective in treating cocaine dependence. This project will test the influence of buspirone maintenance on the reinforcing effects of cocaine in the human laboratory to further demonstrate its potential efficacy in cocaine use disorders.