RIVASTIGMINE AS A TREATMENT FOR METHAMPHETAMINE DEPENDENCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们最近完成了一项双盲、安慰剂对照的人体实验室研究，证明用低剂量的乙酰胆碱酯酶(AChE)抑制剂利瓦斯汀治疗可以减少甲基苯丙胺(MA)诱导的渴求(见图2的初步研究)。这一发现与临床前报告一致，即AChE抑制剂多奈哌齐减少了暴露于非偶然剂量MA后的大鼠的MA寻求行为(Hiranita等人。2006)。为了扩展我们的临床发现，我们建议进行一项为期3年的人体实验室研究，以评估更高剂量的利瓦斯明对MA诱导的渴求和MA自我给药的影响。 我们最近完成的工作表明，在实验室里，3毫克的利瓦斯明可以减轻MA诱导的饥饿感。考虑到更高的剂量会对烟碱型乙酰胆碱(ACh)受体产生更大的抑制作用(用于治疗阿尔茨海默病S病)，因此可以合理地预测，6 mg和12 mg将对渴望和其他强化措施有更显著的影响。这项人体实验室研究是评估利凡斯明作为MA依赖潜在治疗方法的关键下一步。 我们建议只包括表现出MA诱导渴望的参与者，通过在入院前筛选潜在参与者(基于初步研究的标准，图5)。选择表现MA诱导的渴求的参与者将有助于评估利瓦斯明对渴求的影响。 主要目的：研究利凡士的明(0、3、6 mg)对实验性冰毒(0、15、30 mg，IV)所致渴求的治疗作用。 次要目标：研究利凡士的明(0、3和6 mg)治疗对自我给药范例中冰毒选择的影响。 治疗MA依赖需要新的药物开发策略 全世界使用苯丙胺类兴奋剂的人比使用大麻以外的任何非法药物的人都多，MA滥用和依赖是美国增长最快的毒品问题。我们的研究小组最近完成了使用司来吉兰治疗MA依赖的潜在药物的安全性和初步疗效试验(牛顿等人。2005a)、安非他酮(牛顿等人2005年d；2006年)、阿立哌唑(2005年在SFN上提交的数据)和培哚普利(2006年在CPDD上提交的数据)。尽管有这些努力，但在确定治疗MA依赖的有效药物疗法方面仍有许多工作要做。 MA的神经生物学作用无疑包括多巴胺(DA)、5-羟色胺和去甲肾上腺素，但也包括胆碱能神经递质系统的改变。以ACh为靶点的候选化合物是具有吸引力的开发选择，但尚未得到足够的关注。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We recently completed a double-blind placebo-controlled human laboratory study demonstrating that treatment with a low dose of the acetylcholinesterase (AChE) inhibitor rivastigmine reduced methamphetamine (MA)-induced craving (see Preliminary Studies, Fig. 2). This finding is consistent with the preclinical report indicating that the AChE inhibitor donepezil reduced MA-seeking behavior in rats following exposure to a non-contingent dose of MA (Hiranita et al. 2006). To extend our clinical findings, we propose a 3-year human laboratory study to evaluate effects of higher doses of rivastigmine on MA-induced craving and on self-administration of MA. Our recently completed work indicates that 3mg rivastigmine attenuated MA-induced craving in the laboratory. Given that higher dosages of this produce greater inhibition of nicotinic acetylcholine (ACh) receptors (in the treatment of Alzheimer s disease), it is reasonable to predict that 6mg and 12mg will have more pronounced effects on craving and other measures of reinforcement. This human laboratory study is a critical next step in the evaluation of rivastigmine as a potential treatment for MA dependence. We propose to include only participants exhibiting MA-induced craving by screening potential participants prior to admission (criterion based upon Preliminary Studies, Fig. 5). Selection of participants demonstrating MA-induced craving will facilitate assessment of effects of rivastigmine on craving. Primary Objective:To characterize the effects of treatment with rivastigmine (0, 3, and 6 mg) on craving produced by experimental administration of METH (0, 15 and 30mg, IV). Secondary Objective:To characterize the effects of treatment with rivastigmine (0, 3, and 6 mg) on choices for METH exhibited in a self-administration paradigm. Novel Medication Development Strategies for MA Dependence Are Needed More people worldwide use amphetamine-type stimulants than any illicit drug besides cannabis, and MA abuse and dependence is the fastest growing drug problem in the United States. Our research group has recently completed safety and preliminary efficacy trials of potential medications for treating MA dependence using selegiline (Newton et al. 2005a), bupropion (Newton et al. 2005d; 2006), aripiprazole (data presented at SFN 2005), and perindopril (data presented at CPDD 2006). Despite these efforts, much work remains in identifying an effective pharmacotherapy for MA dependence. The neurobiological actions by MA unquestionably involve dopamine (DA), serotonin, and norepinepherine, but also include alterations to cholinergic neurotransmitter systems. Candidate compounds that target ACh are attractive options for development that have not received adequate attention.