A Human Laboratory Study to Investigate Buspirone for Cocaine Use Disorders

描述(申请人提供)：可卡因使用障碍是一个无情的公共卫生问题。密集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，治疗效果随着时间的推移而减少。开发一种药物疗法来提高这些干预措施的疗效是国家药物滥用研究所的优先事项。在中枢神经系统中，可卡因阻止再摄取并诱导多巴胺和5-羟色胺的释放，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。丁螺环酮是一种滥用潜力有限的抗焦虑药物，它是多巴胺自身受体的拮抗剂，也是5-HT1a受体的部分激动剂；这两种受体在可卡因的滥用相关效应中都发挥着关键作用。多巴胺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多巴胺的释放。此外，具有部分激动剂活性的药物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。尽管丁螺环酮产生的药理作用可能有助于治疗可卡因依赖，但我们还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影响的影响，考虑到这种研究可以在进行大规模临床试验之前有效地筛选潜在药物，这在文献中是一个显著的差距。这项研究将评估可卡因在丁螺环酮维持过程中的强化、受试者分级、认知、表现和生理影响。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在控制可卡因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可卡因药物开发努力的范式，超越对多巴胺系统的关注。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。

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.