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的显著持续和选择性作用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，发展有效的药物疗法仍然是国家药物开发协会的一个高度优先事项。在初步研究中，我们发现，在恒河猴中，用适量的单胺释放剂安非他明和PHENMETRAZINE进行慢性治疗，可以在长达28天的时间里，对可卡因和食物维持的反应产生稳健和选择性的减少。我们从猴子身上得到的结果的关键要素已经被其他人在人类实验室研究和临床试验中证实。我们相信这些发现支持了单胺释放剂作为可卡因依赖激动剂候选药物值得进一步研究的主张。为此，本申请提出了两个特定目的，以评估单胺释放效应的环境和药理学决定因素。具体目标1将检查环境和药物史背景对芬美拉嗪诱导的可卡因自我给药减少的影响。特异性Aim 1a将在可选强化剂可用性条件下评估苯美特拉明的作用。在临床药物滥用治疗中，药物治疗越来越多地与引入和控制替代强化剂的可用性的应急管理技术结合使用。我们建议对药物治疗和替代强化剂的双重使用进行建模，并假设替代强化剂的可用性将增强苯美拉嗪诱导的对可卡因自我给药的抑制。特异性Aim 1b将评估苯美特拉明在长期获取和戒断可卡因条件下的作用。在其他药物类别（如阿片类药物）中，获得机会的扩大促进了药物消费的增加、身体依赖的发展以及停药期间药物强化的加强。此外，阿片类激动剂药物在戒断条件下最有效。我们假设，延长获取和戒断可卡因的时间同样会增强苯美拉嗪减少可卡因自我给药的能力。特异性目标2将检查单胺释放效应的药代动力学和药效学决定因素。特异性Aim 2a将关联PHENDIMETRAZINE的药代动力学和行为效应，PHENDIMETRAZINE是一种phenmetrazine前药和附表III兴奋剂。我们假设苯甲美特拉明将保留苯甲美特拉明选择性减少可卡因自我给药的能力，但苯甲美特拉明将有一个缓慢的开始作用，这与苯甲美特拉明活性代谢物的产生有关。特异性Aim 2b将评估一系列单胺释放剂在释放多巴胺和血清素与去甲肾上腺素的选择性上的变化。我们假设，降低去甲肾上腺素能作用的释放剂会减少滥用的可能性，但保留选择性减少可卡因自我给药的能力。

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.