RIVASTIGMINE AND HUPERZINE A AS TREATMENTS FOR COCAINE DEPENDENCE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要乙酰胆碱(ACh)参与大脑奖赏和学习，ACh的改变可能导致物质滥用障碍。可卡因产生的增强效应部分来自中脑多巴胺能神经元释放多巴胺(DA)。刺激ACh传入可以增加伏隔核中DA的释放--伏隔核是参与可卡因产生奖赏效应的关键脑区。乙酰胆碱酯酶(AChE)抑制剂阻断猴子的可卡因自我给药(Wilson和Schuster 1973)，阻断小鼠的可卡因位置偏爱和运动敏化(Hiysta等人)。2003)，并阻止因暴露于甲基苯丙胺(冰毒)而导致的大鼠恢复(Hiranita等人。2006)。 综上所述，这些数据表明，增加ACh的活性可能会减少人类对冰毒的渴望。我们的实验室最近完成了一项研究，以确定AChE抑制剂利瓦斯明对冰毒所产生的自我报告的主观影响的影响(De La Garza等人。2008a；De La Garza等人。2008b)(另见初步研究)。我们发现，静脉注射冰毒(30 Mg)显著增加了自我报告的对冰毒的欲望，而利瓦斯明治疗则取消了这种反应。这一发现表明，进一步研究这类有希望的化合物作为兴奋剂成瘾的治疗方法是有必要的。 为此，我们提出了一种双盲、安慰剂对照的组间相互作用评估方法，评估可卡因与口服利瓦斯汀之间以及可卡因与口服石杉碱甲(HupA)之间的相互作用。 一、假说 1.与接受安慰剂治疗的参与者相比，使用利凡斯明或HupA治疗将减少可卡因引发的渴望和对可卡因的选择。 2.(A)与接受安慰剂治疗的参与者相比，使用利凡斯明或HupA治疗将减少可卡因引起的心率和血压增加。 (B)与接受安慰剂治疗的参与者相比，使用利凡斯明或HupA治疗不会增加可卡因产生的不良事件。 3.(A)相对于接受安慰剂治疗的参与者，使用利瓦斯汀治疗，而不是 HupA，将与可卡因水平的增加相关。 (B)与接受安慰剂治疗的参与者相比，使用利凡斯明而不是HupA的治疗将伴随着更多的淫羊藿碱和苯甲酰ecGonine的形成，以及减少ecGonine甲酯的形成。 二、具体目标 1.在依赖可卡因、不寻求治疗的参与者中，与安慰剂相比，确定利瓦斯明(每天3或6毫克)或HupA(每天0.4或0.8毫克)减少可卡因诱导的渴望(0、20和40毫克，静脉注射)的能力，并减少可卡因产生的增强效应(20毫克，静脉滴注)。 2.确定在实验室环境下接受可卡因依赖的受试者中利凡斯明和HupA的安全性。 3.确定抑制AChE对血浆可卡因及其代谢产物水平的影响。 公共卫生意义：可卡因滥用是一个重要的健康问题，与严重的医疗、精神、社会和经济后果有关。目前还没有预防可卡因成瘾患者复发的药物，预计利瓦斯明和HupA等化合物对这一适应症有用。HupA的测试特别令人兴奋，因为它具有抗氧化和神经保护特性，这也可能有助于它作为治疗可卡因依赖的药物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Acetylcholine (ACh) is involved in brain reward and learning, and changes to ACh may contribute to substance abuse disorders. The reinforcing effects produced by cocaine arise, in part, from release of dopamine (DA) in midbrain dopaminergic neurons. Stimulation of ACh inputs can increase DA release in the nucleus accumbens - a critical brain area involved in the rewarding effects produced by cocaine. ACh-esterase (AChE) inhibitors block cocaine self-administration in monkeys (Wilson and Schuster 1973), block cocaine place preference and locomotor sensitization in mice (Hikida et al. 2003), and block reinstatement induced by exposure to methamphetamine(METH) in rats (Hiranita et al. 2006). Taken together, these data suggest that increasing ACh activity may reduce METH craving in humans. Our lab recently completed a study to determine the effects of the AChE inhibitor rivastigmine on the self-reported subjective effects produced by METH (De La Garza et al. 2008a; De La Garza et al. 2008b)(see also Preliminary Studies). We found that METH (30 mg, IV) administration significantly increased self-reported Desire for METH, and treatment with rivastigmine abolished this response. This finding suggests that further research on this promising class of compounds as treatments for stimulant addiction is warranted. To this end, we propose a double-blind, placebo-controlled, between-groups evaluation of interactions between cocaine and oral rivastigmine and between cocaine and oral huperzine A (HupA). I. HYPOTHESIS 1. Relative to placebo-treated participants, treatment with rivastigmine or HupA will reduce cocaine-induced craving and choices for cocaine. 2. (a)Relative to placebo-treated participants, treatment with rivastigmine or HupA will reduce cocaine-induced increases in heart rate and blood pressure. (b) Relative to placebo-treated participants, treatment with rivastigmine or HupA will not increase the adverse events produced by cocaine. 3. (a) Relative to placebo-treated participants, treatment with rivastigmine, but not HupA, will associated with increased levels of cocaine. (b) Relative to placebo-treated participants, treatment with rivastigmine, but not HupA, will be associated with increased formation of ecgonine and benzoylecgonine, and decreased formation of ecgonine methylester. II. SPECIFIC AIMS 1. Among cocaine-dependent, non-treatment seeking participants, to establish the ability of rivastigmine (3 or 6 mg, daily) or HupA (0.4 or 0.8 mg, daily), as compared to placebo, to reduce cocaine-induced craving (0, 20, and 40 mg, IV) and to reduce reinforcing effects produced by cocaine (20 mg, IV/infusion). 2. To determine the safety of rivastigmine and HupA in cocaine-dependent participants who receive cocaine in a laboratory setting. 3. To determine the effects of AChE inhibition on plasma levels of cocaine and cocaine metabolites. Public Health Significance: Cocaine abuse is an important health problem that is associated with serious medical, psychiatric, social, and economic consequences. No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and compounds such as rivastigmine and HupA are predicted to be useful for this indication. The testing of HupA is particularly exciting since it has antioxidant and neuroprotective properties that may also contribute to its efficacy as a treatment medication for cocaine dependence.