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。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，这些干预措施并不普遍有效，治疗效果随着时间的推移而减弱。国家药物滥用研究所的一个优先事项是开发一种药物疗法，以提高这些干预措施的效力。在中枢神经系统中，可卡因阻断多巴胺和5-羟色胺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靶向这两种神经递质。丁螺环酮是一种抗焦虑药物，滥用潜力有限，是多巴胺自身受体的拮抗剂和5-羟色胺5-HT 1A受体的部分激动剂;这两种受体在可卡因的滥用相关作用中起关键作用。多巴胺自身受体稳定多巴胺能紧张，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用于管理阿片样物质和尼古丁使用障碍的有价值的工具，因为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）。虽然丁螺环酮产生的药理作用可能有利于治疗可卡因依赖，但我们不知道任何人类实验室研究已经测试了丁螺环酮对可卡因行为效应的影响，考虑到此类研究可以有效地筛选潜在的药物，在进行大规模临床试验之前，这是文献中的一个显著空白。本研究将评估可卡因在丁螺环酮维持期间的强化、受试者评级、认知、性能和生理作用。通过确定丁螺环酮如何影响可卡因的行为效应，我们将提供有关这种化合物用于管理可卡因使用障碍的潜在功效的重要证据。这些结果将有助于拓宽目前可卡因药物开发工作的临床神经科学范式，而不仅仅是关注多巴胺系统。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。 公共卫生相关性：一个成功的药物辅助治疗可卡因使用障碍可能需要目标比多巴胺系统。丁螺环酮是一种滥用潜力有限的抗焦虑药，是一种5-羟色胺5 HT 1A受体部分激动剂和多巴胺自身受体拮抗剂，可能有效治疗可卡因依赖。该项目将在人类实验室中测试丁螺环酮维持对可卡因强化作用的影响，以进一步证明其在可卡因使用障碍中的潜在疗效。

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.