Medications Development for Stimulant Abuse

描述(由申请人提供)：这是一项新的R01申请，旨在评估单胺释放剂对恒河猴可卡因自我给药显著持续和选择性影响的临床相关决定因素。可卡因滥用仍然是一个主要的药物滥用问题，开发有效的药物疗法仍然是NIDA的高度优先事项。在初步研究中，我们发现，在恒河猴中，长期服用中等剂量的单胺释放剂苯丙胺和苯美曲津，在长达28天的时间里，可卡因与食物维持反应的强劲和选择性减少。我们对猴子的研究结果的关键因素已经被其他人在人体实验室研究和临床试验中证明了。我们认为这些发现支持单胺释放剂作为可卡因依赖的候选激动剂药物值得进一步研究的主张。为此，本申请提出了两个具体目标来评估单胺释放剂效应的上下文和药理学决定因素。具体目标1将审查环境和药物历史背景对苯美曲津诱导的可卡因自我给药减少的影响。具体目标1a将在替代增强剂可用的条件下评估苯美拉津的效果。在临床药物滥用治疗中，药物疗法越来越多地与应急管理技术结合使用，这些技术引入并控制替代增强剂的可用性。我们建议模拟这种药物疗法和替代增强剂的双重使用，我们假设替代增强剂的可用性将增强苯美曲津诱导的可卡因自我给药抑制。具体目标1b将评估在延长可卡因接触和戒断条件下苯美曲津的效果。在其他药物类别(如阿片类药物)中，扩大使用范围会增加药物消费，促进身体依赖的发展，并在戒断期间加强药物的使用。此外，阿片类激动剂药物在戒断条件下最有效。我们假设，扩大可卡因的获取和戒除同样会增强苯美曲津减少可卡因自我给药的能力。具体目标2将检查单胺释放剂效应的药代动力学和药效学决定因素。具体目标2a将把苯美特拉津的药代动力学和行为效应联系起来，苯美特拉嗪是一种前药，也是一种时间表III的兴奋剂。我们假设，在可卡因自身给药过程中，苯二甲肼将保留苯美曲津产生选择性减少的能力，但苯二甲肼将具有与活性苯美特拉津代谢物的产生相关的缓慢起效。具体目标2b将评估一系列单胺释放剂与去甲肾上腺素相比，它们在释放多巴胺和5-羟色胺方面的选择性不同。我们假设，去甲肾上腺素作用降低的释放剂将显示出减少的滥用倾向，但保留了选择性减少可卡因自我给药的能力。 公共卫生相关性：可卡因滥用仍然是一个主要的公共卫生问题，开发有效的药物疗法仍然是NIDA的高度优先事项。该申请提出了一系列临床前研究，以评估可能影响单胺释放剂作为候选激动剂药物的背景和药理学因素。这些研究可能有助于(A)更有效地实施现有的单胺释放剂作为激动剂药物，以及(B)开发更安全的药物，减少滥用的可能性。

DESCRIPTION (provided by applicant): This is a new R01 application designed to evaluate clinically relevant determinants of the remarkably sustained and selective effects of monoamine releasers on cocaine self-administration in rhesus monkeys. Cocaine abuse remains a major drug abuse problem, and the development of effective pharmacotherapies continues to be a high priority for NIDA. In preliminary studies, we have found that chronic treatment with modest doses of the monoamine releasers amphetamine and PHENMETRAZINE produced robust and selective reductions in cocaine- vs. food-maintained responding for up to 28 days in rhesus monkeys. Key elements of our results from monkeys have been demonstrated by others in human laboratory studies and clinical trials. We believe these findings support the proposition that monoamine releasers warrant further study as candidate agonist medications for cocaine dependence. Toward that end, this application proposes two Specific Aims to evaluate contextual and pharmacologic determinants of monoamine releaser effects. Specific Aim 1 will examine effects of environmental and drug-history contexts on phenmetrazine-induced reductions in cocaine self-administration. Specific Aim 1a will evaluate phenmetrazine effects under conditions of alternative reinforcer availability. In clinical drug abuse treatment, pharmacotherapies are increasingly used in conjunction with contingency management techniques that introduce and control availability of alternative reinforcers. We propose to model this dual use of pharmacotherapies and alternative reinforcers, and we hypothesize that alternative reinforcer availability will enhance phenmetrazine-induced suppression of cocaine self- administration. Specific Aim 1b will evaluate phenmetrazine effects under conditions of extended access to and withdrawal from cocaine. In other drug classes (e.g. opioids), extended access promotes increased drug consumption, the development of physical dependence, and heightened drug reinforcement during withdrawal. Moreover, opioid agonist medications are most effective under conditions of withdrawal. We hypothesize that extended access to and withdrawal from cocaine will similarly enhance the ability of phenmetrazine to reduce cocaine self-administration. Specific Aim 2 will examine pharmacokinetic and pharmacodynamic determinants of monoamine releaser effects. Specific Aim 2a will correlate pharmacokinetic and behavioral effects of PHENDIMETRAZINE, a phenmetrazine prodrug and Schedule III stimulant. We hypothesize that phendimetrazine will retain phenmetrazine's ability to produce selective decreases in cocaine self- administration, but that phendimetrazine will have a slow onset of action that correlates with generation of the active phenmetrazine metabolite. Specific Aim 2b will evaluate a series of monoamine releasers that vary in selectivity to release dopamine and serotonin vs. norepinephrine. We hypothesize that releasers with reduced noradrenergic effects will display reduced abuse liability but retain an ability to produce selective reductions in cocaine self-administration. PUBLIC HEALTH RELEVANCE: Cocaine abuse remains a major public health problem, and the development of effective pharmacotherapies continues to be a high priority for NIDA. This application proposes a series of preclinical studies to assess contextual and pharmacologic factors that may influence the utility of monoamine releasers as candidate agonist medications. These studies may contribute to both (a) more effective implementation of existing monoamine releasers as agonist medications, and (b) the development of safer medications with reduced abuse liability.