Cocaine and Polydrug Abuse: New Medication Strategies

这是NIDA计划项目(P-01)的新申请，题为可卡因和多药滥用：新的用药策略。可卡因滥用仍然是美国最严重的药物滥用问题之一，到目前为止，还没有有效的反可卡因药物。可卡因经常与海洛因一起滥用，对可卡因和阿片类药物的双重依赖使以药物为基础的治疗进一步复杂化。提出了四个相互关联的临床和临床前研究项目，以开发治疗可卡因滥用和多药滥用的新药。这些多学科合作项目涉及行为科学、内分泌学、神经生物学和药理学。一种创新的快速球(可卡因+海洛因)滥用的临床前新模型将用于评估新的药物策略，并测试针对快速球的可卡因和阿片类药物成分的药物组合将比单独使用抗可卡因或抗阿片类药物治疗更有效的假设。将评估潜在的抗可卡因药物(内分泌调节剂、多巴胺再摄取抑制剂；多巴胺激动剂和拮抗剂)和抗阿片类药物(高、中效MU激动剂和一种新的长效MU拮抗剂)的急性和慢性治疗。除了药理学方法，我们还建议评估减少可卡因滥用的新生物方法，这些方法基于我们最近发现的可卡因-神经内分泌相互作用。我们假设可卡因的急性神经内分泌效应可能有助于其滥用相关效应，分析可卡因-内分泌相互作用将指导药物开发的新策略。可卡因对垂体前叶、性腺和肾上腺激素的刺激之间的时间相关性将在临床和临床前研究中进行检验。可卡因急性内分泌效应的行为相关性将在临床研究和临床前研究可卡因滥用治疗的生物方法中进行评估。在临床前研究中，将使用选择性单胺激动剂和拮抗剂来评估可卡因急性内分泌作用的药理学机制。此外，我们建议有系统地研究因以下原因而产生的可卡因急性内分泌模式的变化：(A)大量服用可卡因；(B)在可卡因中加入海洛因以模拟治疗可卡因滥用药物的疗效。这些研究应该澄清可卡因滥用影响神经内分泌因素并受其影响的方式。在了解药物滥用相关影响的神经生物学决定因素方面的进展应有助于开发更有效的治疗药物。

This is a new application for a NIDA Program Project (P-01) entitled Cocaine and Polydrug Abuse: New Medication Strategies. Cocaine abuse remains one of the nation's most serious drug abuse problems, and as yet, there are no effective anti-cocaine medications. Cocaine is often abused in combination with heroin, and dual dependence on cocaine and opioids further complicates medication based treatment. Four inter- related clinical and pre-clinical research projects are proposed to develop novel medications for the treatment of cocaine abuse and polydrug abuse. These multi-disciplinary collaborative projects involve behavioral science, endocrinology, neurobiology and pharmacology. An innovative new preclinical model of speedball (cocaine+heroin) abuse will be used to evaluate novel medication strategies, and to test the hypothesis that medication combinations targeted at both the cocaine and the opioid components of the speedball will be more effective than treatment with either anti-cocaine or anti-opioid medications alone. Acute and chronic treatment with potential anti-cocaine medications (endocrine modulators, dopamine reuptake inhibitors; dopamine agonists and antagonists ) and anti-opioid medications (high and intermediate efficacy mu agonists and a new long-acting mu antagonist) will be evaluated. In addition to pharmacological approaches, we propose to evaluate novel biologic approaches to reduce cocaine abuse that are based on our recent discoveries of cocaine-neuroendocrine interactions. We hypothesize that the acute neuroendocrine effects of cocaine may contribute to its abuse- related effects and that analysis of cocaine-endocrine interactions will guide new strategies for medications development. The temporal covariance between cocaine stimulation of anterior pituitary, gonadal and adrenal hormones will be examined in both clinical and preclinical studies. The behavioral relevance of cocaine's acute endocrine effects will be evaluated both in clinical studies and preclinical studies of biologic approaches to cocaine abuse treatment. The pharmacological mechanisms underlying cocaine's acute endocrine effects will be evaluated with selective monoamine agonists and antagonists in preclinical studies. In addition, we propose to systematically examine changes in the acute endocrine profile of cocaine produced by (a) repeated cocaine dosing in a binge pattern, (b) the addition of heroin to cocaine to simulate milieu on the efficacy of medications for cocaine abuse treatment will e examined. These studies should clarify the ways in which cocaine abuse influences and is influenced by neuroendocrine factors. Advances in understanding the neurobiological determinants of the abuse-related effects of drugs should facilitate the development of more effective treatment medications.