Rivastigmine and Huperzine A as Potential Treatments for Cocaine Addiction

描述（由申请人提供）：乙酰胆碱（ACh）参与大脑奖励和学习功能，对这种神经递质系统的扰动可能导致药物滥用障碍。动物研究表明，毒蕈碱类乙酰胆碱酯酶受体在可卡因增强和非增强反应中的重要性，乙酰胆碱酯酶（AChE）抑制剂减少了啮齿动物寻求甲基苯丙胺的行为。与这些发现一致，我们小组最近完成的一项双盲安慰剂对照研究表明，在实验室中，乙酰胆碱酯酶抑制剂利瓦斯汀治疗可以减少甲基苯丙胺引起的渴望。在本申请中，我们提出了一项人体实验室研究，以评估在可卡因依赖、不寻求治疗的参与者中，利瓦斯汀（3或6毫克，每天）或石杉碱a（0.4或0.8毫克，每天）对可卡因产生的渴望和强化效应的影响。利瓦斯汀是一种氨基甲酸酯衍生物，对AChE和BuChE均有相同的抑制作用，并且对中枢活性有选择性。石杉碱A是本次修订申请的创新药物选择，来源于中药石杉。石杉碱A是一种有效的胆碱酯酶抑制剂，并在大脑中具有其他几种作用（通过DA， NMDA和GABA，以及抗氧化作用和神经保护），这可能最终有助于其功效。在拟议的研究中，我们将只包括随机化之前表现出可卡因诱导渴望的参与者；一种预测提高统计能力以检测药物治疗对这种特定症状的影响的策略。拟议项目的公共卫生意义是显而易见的。目前还没有药物可用于预防可卡因成瘾患者的复发，AChE抑制剂预计可用于这一适应症。公共卫生相关性：目前没有药物可用于预防可卡因成瘾患者的复发，预计乙酰胆碱酯酶抑制剂可用于这一适应症。为此，我们提出了一项人体实验室研究，以评估利瓦斯丁明或石杉碱a对可卡因产生的渴望和强化效应的影响。

DESCRIPTION (provided by applicant): Acetylcholine (ACh) is involved in brain reward and learning functions, and perturbations to this neurotransmitter system may contribute to substance abuse disorders. Animal studies have shown the importance of muscarinic ACh receptors in cocaine reinforced- and non-reinforced-responding, and acetylcholinesterase (AChE) inhibitors reduced methamphetamine-seeking behavior in rodents. Consistent with these findings, a recently completed double-blind placebo-controlled study from our group demonstrated that treatment with the AChE inhibitor rivastigmine reduced craving produced by administration of methamphetamine in the laboratory. In this application, we propose a human laboratory research to evaluate the effects of rivastigmine (3 or 6 mg, daily) or huperzine A (0.4 or 0.8 mg, daily) on craving and reinforcing effects produced by administration of cocaine in cocaine-dependent, non-treatment seeking participants. Rivastigmine is a carbamate derivative that inhibits both AChE and BuChE with equal potency and has selectivity for central activity. Huperzine A is an innovative drug choice for this revised application and is derived from the Chinese herb Huperzia serrata. Huperzine A is a potent cholinesterase inhibitor, and has several other effects in brain (via DA, NMDA and GABA, as well as antioxidant effects and neuroprotection) that may ultimately contribute to its efficacy. In the proposed studies, we will include only participants exhibiting cocaine-induced craving prior to randomization; a strategy predicted to increase statistical power to detect effects of medication treatment on this specific symptom. The public health significance of the proposed project is clear. No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and AChE inhibitors are predicted to be useful for this indication. PUBLIC HEALTH RELEVANCE: No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and acetylcholinesterase inhibitors are predicted to be useful for this indication. To this end, we propose a human laboratory research study to evaluate the effects of rivastigmine or huperzine A on craving and reinforcing effects produced by administration of cocaine.