RIVASTIGMINE AND HUPERZINE A AS TREATMENTS FOR COCAINE DEPENDENCE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 乙酰胆碱（ACh）参与大脑的奖赏和学习，其变化可能导致物质滥用障碍。可卡因产生的强化作用部分来自中脑多巴胺能神经元中多巴胺（DA）的释放。刺激乙酰胆碱输入可以增加多巴胺在脑桥核的释放-一个关键的大脑区域参与可卡因产生的奖励效应。乙酰胆碱酯酶（AChE）抑制剂可阻断猴的可卡因自我给药（Wilson和Schuster，1973年），阻断小鼠的可卡因位置偏好和运动致敏（Hikida等人，2003年），并阻断大鼠因接触甲基苯丙胺（METH）而诱发的复发（Hiranita等人，2006年）。 总之，这些数据表明，增加乙酰胆碱活性可能会减少人类对甲基苯丙胺的渴望。我们实验室最近完成了一项研究，以确定AChE抑制剂rivastigmine对METH产生的自我报告主观效应的影响（De La Garza et al. 2008 a; De La Garza et al. 2008 b）（另见初步研究）。我们发现METH（30 mg，IV）给药显著增加了自我报告的METH欲望，rivastigmine治疗消除了这种反应。这一发现表明，进一步研究这类有前途的化合物作为治疗兴奋剂成瘾是必要的。 为此，我们提出了一个双盲，安慰剂对照，组间评价可卡因和口服卡巴拉汀之间的相互作用，可卡因和口服石杉碱甲（石杉碱甲）。 I. 假设 1. 相对于安慰剂治疗的受试者，rivastigmine或HupA治疗将减少可卡因诱导的对可卡因的渴望和选择。 2. （a）相对于安慰剂治疗的受试者，rivastigmine或HupA治疗将减少可卡因诱导的心率和血压升高。 (b)相对于安慰剂治疗的受试者，rivastigmine或HupA治疗不会增加可卡因产生的不良事件。 3. (a)相对于安慰剂治疗的受试者，rivastigmine治疗，但 HupA与可卡因水平的增加有关。 (b)相对于安慰剂治疗的受试者，rivastigmine治疗，但 HupA将与芽子碱和苯甲酰芽子碱的形成增加以及芽子碱甲酯的形成减少相关。 二. 具体目标 1. 在可卡因依赖、非寻求治疗的受试者中，确定rivastigmine（3或6 mg，每日一次）或HupA（0.4或0.8 mg，每日一次）与安慰剂相比减少可卡因诱导的渴求（0、20和40 mg，IV）和减少可卡因产生的强化效应（20 mg，IV/输注）的能力。 2. 确定卡巴拉汀和HupA在实验室环境中接受可卡因的可卡因依赖受试者中的安全性。 3. 确定乙酰胆碱酯酶抑制对可卡因和可卡因代谢物血浆水平的影响。 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。 目前没有药物可用于预防可卡因成瘾患者的复发，预计rivastigmine和HupA等化合物可用于该适应症。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，这也可能有助于其作为可卡因依赖治疗药物的功效。

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.