Rivastigmine as a Treatment for Methamphetamine Dependence

描述（由申请人提供）：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。针对乙酰胆碱的药物作为MA依赖的治疗尚未得到足够的关注。我们最近完成了一项双盲安慰剂对照的人体实验室研究，证明使用3 mg剂量的乙酰胆碱酯酶（AChE）抑制剂rivastigmine治疗可显著减弱MA诱导的渴求。这一发现与临床前报告一致，该报告表明，在暴露于非偶然剂量的MA后，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结果，我们提出了一项为期3年的人体实验室研究，以评价较高剂量的rivastigmine对MA诱导的渴求和MA自我给药的影响。为了确保受试者具有目标症状，我们建议在随机化之前筛选受试者，并将仅在实验室中保留表现出MA诱导的渴望的受试者。将使用调查问卷和静脉自我给药程序评估卡巴拉汀对MA增强作用的影响。该项目的目的如下：在非寻求治疗的MA依赖性志愿者中，表征rivastigmine（0、3、6或12 mg）治疗对MA（0、15和30 mg，IV）实验性给药产生的渴求的影响。假设1.卡巴拉汀治疗将剂量依赖性地减少MA诱导的渴望。假设2.在自我给药模式中，卡巴拉汀治疗将减少MA的选择。拟议的工作代表了一个重要的研究工作，具有相当大的公共卫生意义，因为它将建立一个程序，用于评估化合物，特别是针对烟碱乙酰胆碱受体激活治疗MA依赖。所获得的知识可能最终支持MA依赖循证治疗的开发和实施，这是一个具有巨大公共卫生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.