Rivastigmine as a Treatment for Methamphetamine Dependence

卡巴拉汀治疗甲基苯丙胺依赖

• 批准号: 7351283
• 负责人: Richard De La Garza
• 金额: $ 38.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351283
• 关键词: Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Admission activity; Alzheimer' s Disease; Attention; Attenuated; Behavior; Cholinergic Agents; Clinical; Data; Dependence; Development; Dopamine; Dose; Double-Blind Method; Drug abuse; Ensure; Evaluation; Evidence based treatment; Exhibits; Exposure to; Figs - dietary; Human; Intravenous; Knowledge; Laboratories; Laboratory Study; Measures; Methamphetamine; Neurons; Neurotransmitters; Nicotinic Receptors; Norepinephrine; Participant; Pharmaceutical Preparations; Placebo Control; Procedures; Psychological reinforcement; Public Health; Questionnaires; Randomized; Rattus; Receptor Activation; Reporting; Research; Screening procedure; Self Administration; Symptoms; System; Work; base; cholinergic; craving; donepezil; dosage; pre-clinical; presynaptic; programs; rivastigmine; treatment effect; volunteer

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.

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 依赖的治疗方法尚未受到足够的重视。我们最近完成了一项双盲安慰剂对照人体实验室研究，表明使用 3 毫克剂量的乙酰胆碱酯酶 (AChE) 抑制剂卡巴拉汀治疗可显着减弱 MA 引起的渴望。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，使用乙酰胆碱酯酶抑制剂多奈哌齐治疗可减少大鼠的 MA 寻求行为（Hiranita 等，2006）。为了扩展我们的临床发现，我们提出了一项为期 3 年的人体实验室研究，以评估高剂量卡巴拉汀对 MA 诱发的渴望和自我服用 MA 的影响。为了确保参与者具有目标症状，我们建议在随机化之前对参与者进行筛选，并且只保留在实验室中表现出 MA 引起的渴望的参与者。将通过问卷调查和静脉自我给药程序来评估卡巴拉汀对 MA 增强作用的影响。该项目的目标如下：在非寻求治疗的 MA 依赖志愿者中，表征卡巴拉汀（0、3、6 或 12 毫克）治疗对实验性给予 MA（0、15、和 30mg，IV）。假设 1. 卡巴拉汀治疗会剂量依赖性地减少 MA 引起的渴望。假设 2：卡巴拉汀治疗将减少自我给药范式中 MA 的选择。拟议的工作代表了一项具有重大公共卫生意义的重要研究工作，因为它将建立一个项目，用于评估专门针对烟碱 ACh 受体激活的化合物，以治疗 MA 依赖。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 依赖是一种对公共卫生影响巨大的药物滥用问题。