Rivastigmine and Huperzine A as Potential Treatments for Cocaine Addiction

描述(申请人提供)：乙酰胆碱(ACh)参与大脑奖赏和学习功能，该神经递质系统的扰动可能导致物质滥用障碍。动物研究表明，M受体在可卡因增强和非增强反应中的重要性，而乙酰胆碱酯酶(AChE)抑制剂减少了啮齿类动物的甲基苯丙胺寻找行为。与这些发现一致的是，我们小组最近完成的一项双盲安慰剂对照研究表明，使用AChE抑制剂利瓦斯明治疗可以减少实验室中服用甲基苯丙胺所产生的渴求。在这项申请中，我们提出了一项人体实验室研究，以评估利瓦斯明(每天3或6毫克)或石杉碱甲(每天0.4或0.8毫克)对可卡因依赖、非寻求治疗参与者的渴求和增强作用的影响。利瓦斯明是一种氨基甲酸酯类化合物，对AChE和BuChE具有同等效力的抑制作用，并具有中枢活性的选择性。石杉碱甲是这一修订应用的创新药物选择，它是从中草药石杉中提取的。石杉碱甲是一种有效的胆碱酯酶抑制剂，在大脑中还有其他几种作用(通过DA、NMDA和GABA，以及抗氧化和神经保护作用)，最终可能有助于其疗效。在拟议的研究中，我们将只包括在随机化之前表现出可卡因诱导渴望的参与者；这一策略预计将增加统计能力，以检测药物治疗对这一特定症状的影响。拟议的项目对公共卫生的意义是显而易见的。目前还没有预防可卡因成瘾患者复发的药物，预计AChE抑制剂对这一适应症有用。公共卫生相关性：目前还没有预防可卡因成瘾患者复发的药物，预计乙酰胆碱酯酶抑制剂对这一适应症有用。为此，我们提出了一项人体实验室研究，以评估利瓦斯明或石杉碱甲对服用可卡因产生的渴求和增强效果的影响。

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.