Nicotinic Modulation of Methamphetamine's Behavioral and Neurochemical Effects

描述（由申请人提供）：本R21申请响应PA-07-227，该申请描述了对甲基苯丙胺（MA）和可卡因成瘾效应中潜在神经生物学和行为机制的迫切需求。MA和可卡因的使用和滥用是全世界的一个重大公共卫生问题；尽管在确定间接和直接作用于多巴胺（DA）的候选药物作为潜在的激动剂治疗方面做出了巨大的努力，但目前还没有有效的药物治疗方法可用于治疗MA和可卡因成瘾。由于非多巴胺能机制，包括尼古丁系统，也可能对这些精神运动兴奋剂药物的成瘾作用起重要作用，对非多巴胺能配体，包括尼古丁药物的研究，可能会导致新的“基于激动剂”的候选药物。根据科学文献的报道和我们自己的初步结果，尼古丁激动剂可以干扰MA的行为和神经化学效应的表达，因此，可能是合适的“基于激动剂”的兴奋剂滥用和成瘾的候选药物。为了评估这种药物策略，我们建议确定原型激动剂尼古丁（NIC）是否会减弱灵长类动物滥用MA相关的行为和神经化学效应。利用已建立的方法研究多巴胺能药物的区别刺激和可观察效应，我们计划直接分析急性或慢性（15天）尼古丁治疗如何改变MA的行为效应。药物鉴别研究将在准备了针对纹状体或前额皮质的透析管的猴子中进行。在药物测试期间，透析液样本将被移除并分析DA水平。这些协同研究将允许在同一测试阶段内对MA的行为和神经化学效应如何被尼古丁激动剂治疗所改变进行全面评估。这些研究的结果将提供重要的信息，说明基于尼古丁的药物治疗策略在管理滥用和成瘾MA和相关兴奋剂方面的潜在治疗价值。拟议的研究也应该导致进一步的研究，以确定新的尼古丁目标，以帮助对抗MA成瘾。公共卫生相关性：甲基苯丙胺滥用和成瘾已成为一个主要的公共卫生问题，但尚未确定有效的治疗方法来帮助处理这一问题。本项目旨在研究基于尼古丁的药物治疗策略的潜在治疗价值。拟议的研究将导致对甲基苯丙胺成瘾机制的更深入了解，并可能确定新的尼古丁目标，以帮助对抗甲基苯丙胺成瘾。

DESCRIPTION (provided by applicant): This R21 application responds to PA-07-227, which describes an urgent need for a greater understanding of the underlying neurobiological and behavioral mechanisms in the addictive effects of methamphetamine (MA) and cocaine. The use and abuse of MA and cocaine is a major public health concern world-wide; despite significant effort to identify indirectly and directly acting dopamine (DA)-based candidate medications as potential agonist-based treatments, no effective pharmacotherapies are yet available for the management of addiction to MA and cocaine. As non-dopaminergic mechanisms, including nicotinic systems, also may contribute importantly to the addictive effects of these psychomotor stimulant drugs, the study of non- dopaminergic ligands, including nicotinic drugs, may lead to novel 'agonist-based' candidate medications. Based on reports in the scientific literature and our own preliminary results, nicotinic agonists can interfere with the expression of behavioral and neurochemical effects of MA, and therefore, may be suitable 'agonist-based' candidate medications for stimulant abuse and addiction. To evaluate this medication strategy, we propose to determine whether the prototypic agonist nicotine (NIC) attenuates the abuse-related behavioral and neurochemical effects of MA in a primate species. Using established methods to study the discriminative- stimulus and observable effects of dopaminergic drugs, we plan to directly analyze how acute or chronic (15- day) treatment with nicotine may alter behavioral effects of MA. Drug discrimination studies will be conducted in monkeys prepared with dialysis cannulae targeting either the striatum or prefrontal cortex. During drug testing, dialysate samples will be removed and analyzed for DA level. These coordinated studies will allow a comprehensive assessment within the same test session of how the behavioral and neurochemical effects of MA may be modified by nicotinic agonist treatment. The results of these studies will provide important information regarding the potential therapeutic value of nicotinic-based medication strategies for the management of abuse and addiction to MA and related stimulants. The proposed research also should lead to further studies to identify novel nicotinic targets to help combat MA addiction. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse and addiction has emerged as a major public health concern, and effective treatments with which to help manage this problem have not yet been identified. This project is designed to study the potential therapeutic value of nicotinic-based medication strategies. The proposed research will lead to a greater understanding of the mechanisms responsible for methamphetamine addiction and may identify novel nicotinic targets to help combat methamphetamine addiction.