RIVASTIGMINE AS A TREATMENT FOR METHAMPHETAMINE DEPENDENCE

卡巴拉汀治疗甲基苯丙胺依赖

基本信息

批准号：
8166770
负责人：
Richard De La Garza
金额：
$ 6.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8166770
关键词：
Acetylcholine Acetylcholinesterase Inhibitors Admission activity Alzheimer&apos s Disease Amphetamines Attention Attenuated Behavior Bupropion Cannabis Clinical Computer Retrieval of Information on Scientific Projects Database Data Dependence Development Dopamine Dose Double-Blind Method Evaluation Exhibits Exposure to Figs - dietary Funding Grant Human Illicit Drugs Institution Laboratories Laboratory Study Measures Methamphetamine Methamphetamine dependence Neurobiology Neurotransmitters Nicotinic Receptors Participant Perindopril Pharmaceutical Preparations Pharmacotherapy Placebo Control Psychological reinforcement Rattus Reporting Research Research Personnel Resources Safety Screening procedure Selegiline Self Administration Serotonin Source System United States United States National Institutes of Health Work aripiprazole base cholinergic craving donepezil dosage efficacy trial methamphetamine abuse novel pre-clinical rivastigmine treatment effect

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。我们最近完成了一项双盲安慰剂对照人体实验室研究，证明低剂量乙酰胆碱酯酶 (AChE) 抑制剂卡巴拉汀治疗可减少甲基苯丙胺 (MA) 诱发的渴望（参见初步研究，图 2）。这一发现与临床前报告一致，表明乙酰胆碱酯酶抑制剂多奈哌齐可减少暴露于非偶然剂量的 MA 后大鼠的 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。我们最近完成的研究表明，3 毫克卡巴拉汀在实验室中减弱了 MA 引起的渴望。鉴于较高剂量的这种药物会对烟碱乙酰胆碱 (ACh) 受体产生更大的抑制（在阿尔茨海默氏病的治疗中），因此可以合理地预测 6 毫克和 12 毫克将对渴望和其他强化措施产生更明显的影响。这项人体实验室研究是评估卡巴拉汀作为 MA 依赖性潜在治疗方法的关键下一步。我们建议通过在入院前筛选潜在参与者（基于初步研究的标准，图 5），仅纳入表现出 MA 引起的渴望的参与者。选择表现出 MA 引起的渴望的参与者将有助于评估卡巴拉汀对渴望的影响。主要目的：表征卡巴拉汀（0、3 和 6 毫克）治疗对实验性给予冰毒（0、15 和 30 毫克，静脉注射）产生的渴望的影响。次要目标：表征卡巴拉汀（0、3 和 6 mg）治疗对自我给药模式中 METH 选择的影响。需要针对 MA 依赖性的新药物开发策略全世界使用安非他明类兴奋剂的人数比大麻以外的任何非法药物都要多，而苯丙胺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治疗 MA 依赖的潜在药物的安全性和初步疗效试验，使用司来吉兰（Newton 等人，2005a）、安非他酮（Newton 等人，2005d；2006）、阿立哌唑（SFN 2005 上提供的数据）和培哚普利（CPDD 2006 提供的数据）。尽管做出了这些努力，但在寻找治疗 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涉及多巴胺 (DA)、血清素和去甲肾上腺素，但也包括胆碱能神经递质系统的改变。靶向乙酰胆碱的候选化合物是有吸引力的开发选择，但尚未得到足够的重视。