Buspirone as a Candidate Medication for Methamphetamine Abuse

丁螺环酮作为甲基苯丙胺滥用的候选药物

基本信息

批准号：
8650812
负责人：
CRAIG R RUSH
金额：
$ 16.72万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8650812
关键词：
Abstinence Admission activity Adverse effects Agonist American Amphetamines Anti-Anxiety Agents Attenuated Autoreceptors Behavior Therapy Behavioral Benzodiazepines Buspirone Cardiovascular system Cereals Clinical Clinical Research Clinical Trials Communicable Diseases Communities Crime Data Development Disease Dopamine Dopamine Agonists Dopamine D2 Receptor Dose Enrollment Exploratory/Developmental Grant Future Human Impaired cognition Laboratories Laboratory Procedures Laboratory Research Locomotion Maintenance Mediating Medical Methamphetamine Methamphetamine dependence Monkeys Motivation National Institute of Drug Abuse Nausea Nerve Neurosciences Neurotransmitters Nicotine Nicotine Use Disorder Norepinephrine Opioid Participant Patients Performance Pharmaceutical Preparations Pharmacotherapy Phase II Clinical Trials Physiological Play Premature Mortality Probability Procedures Productivity Public Health Reporting Research Resources Rodent Role Safety Sedation procedure Self Administration Serotonin Serotonin Receptor 5-HT1A Synapses System Testing United States Vesicle clinical efficacy clinical practice cost dopamine D3 receptor dopamine system double-blind placebo controlled trial drug reinforcement indexing innovation methamphetamine abuse monoamine novel pre-clinical presynaptic prevent public health relevance receptor reinforcer research study response stereotypy success tool

项目摘要

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.

描述（由申请人提供）：甲基苯丙胺（MA）滥用是不懈的公共卫生问题。尽管行为疗法可有效减少MA使用，但许多入学的患者无法实现大量的禁欲，这表明需要其他策略。尽管美国国家药物滥用研究所（NIDA）和科学和治疗界的广泛努力是高度重视，但尚未确定有效的MA滥用药物。 MA充当单胺转运蛋白的底物，并将其带入神经末端，从而促进了多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）的释放，通过防止储存囊泡中的神经递质的积累和载载载体介导的交换，从而促进了突触的释放。 MA滥用主要归因于其提高突触DA水平的能力。但是，针对DA系统尚未确定用于管理MA滥用的广泛有效的药物治疗。 MA还促进了5-HT释放，该释放介导了MA的增强作用。 MA滥用也以DA和5-HT系统的扰动为特征。因此，除了DA之外，还可能需要针对5-HT系统的有效药物，这是一种创新的策略。 Buspirone（BUSP）是一种有限的滥用潜力的抗焦虑药，是5-羟色胺5-HT1A受体的部分激动剂，DA自动受体的拮抗剂和DA D3受体的选择性拮抗剂。部分激动剂被公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，因为当神经递质张力较低时，当神经递质张力较低时刺激受体（即在禁欲期间），而神经递质张力张力很高（即在失效后）。 DA自动受体稳定多巴胺能张力，在这些受体处的拮抗剂可以增加DA释放。 DA D3受体在吸毒动机中起着至关重要的作用。尽管药理学特征和积极的临床前结果，我们仍未意识到任何人类实验室研究，该研究测试了BUSP对MA滥用相关影响的影响。人类实验室研究可以在进行大规模临床试验之前有效筛选潜在的药物。这项拟议的研究将评估MA在BUSP维护过程中MA的增强，受试者率，性能和生理影响。人类药物增强程序对MA药物疗法的临床功效具有良好的预测有效性。通过确定BUSP如何影响MA的行为影响，我们将提供有关该化合物管理MA使用障碍的潜在功效的重要证据。这些结果将有助于扩大MA药物开发工作的当前临床神经科学范式，而不是关注DA系统。此外，与等待新的分子可以在人类中进行测试相比，证明市售药物的初始功效会更快地影响临床研究。