Rivastigmine as a Treatment for Methamphetamine Dependence

描述(申请人提供)：甲基苯丙胺(MA)直接从突触前神经元释放多巴胺和去甲肾上腺素，但也改变胆碱能神经递质系统的功能。靶向乙酰胆碱的药物作为治疗MA依赖的药物还没有得到足够的重视。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3毫克剂量的乙酰胆碱酯酶(AChE)抑制剂利瓦斯汀治疗显著减轻了MA诱导的渴求。这一发现与一项临床前报告一致，该报告表明，在暴露于非偶然剂量的MA后，用AChE抑制剂多奈哌齐治疗减少了大鼠的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。为了确保参与者有目标症状，我们建议在随机化之前对参与者进行筛选，并将只保留在实验室中表现出MA诱导渴望的参与者。利瓦斯汀对MA强化作用的效果将通过问卷调查和静脉给药程序进行评估。该项目有以下目标：在不寻求治疗、依赖MA的志愿者中，表征利瓦斯明(0、3、6或12 mg)对实验性服用MA(0、15和30 mg，IV)所产生的渴求的影响。假设1：利凡士的明治疗将剂量依赖地减少MA诱导的渴求。假设2：利凡士的明治疗将减少MA在自我给药范例中的选择。这项拟议的工作代表了一项具有相当大公共卫生意义的重要研究努力，因为它将建立一个评估专门针对尼古丁ACh受体激活的化合物治疗MA依赖的计划。所获得的知识可能最终支持针对MA依赖的循证治疗的开发和实施，MA依赖是一种具有巨大公共健康影响的药物滥用问题。

DESCRIPTION (provided by applicant): Methamphetamine (MA) directly releases dopamine and norepinephrine from presynaptic neurons, but also alters the functioning of cholinergic neurotransmitter systems. Medications targeting acetylcholine have not received adequate attention as treatments for MA dependence. We recently completed a double-blind placebocontrolled human laboratory study demonstrating that treatment with a 3mg dose of the acetylcholinesterase (AChE) inhibitor rivastigmine significantly attenuated MA-induced craving. This finding is consistent with a preclinical report indicating that treatment with 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. In order to ensure that participants have the target symptom, we propose to screen participants prior to randomization and will retain only participants exhibiting MA-induced craving in the laboratory. Effects of rivastigmine on the reinforcing effects of MA will be assessed using a questionnaire and using intravenous self-administration procedures. The project has the following objective: In non-treatment-seeking, MA-dependent volunteers, to characterize the effects of treatment with rivastigmine (0, 3, 6, or 12mg) on craving produced by experimental administration of MA (0, 15, and 30mg, IV). Hypothesis 1. Rivastigmine treatment will dose-dependently reduce MA-induced craving. Hypothesis 2. Rivastigmine treatment will reduce choices for MA in a selfadministration paradigm. The proposed work represents an important research effort with considerable public health significance in that it will establish a program for evaluating compounds targeted specifically at nicotinic ACh receptor activation for the treatment of MA dependence. The knowledge gained may ultimately support development and implementation of evidence-based treatments for MA dependence, a drug abuse problem with tremendous public health impact.