Endocannabinoid modulation of methamphetamine sensitization.

描述（申请人提供）：2004年，约有74,000次急诊室就诊和超过150,000次住院是由于滥用甲基苯丙胺（冰毒）。因此，对有效的甲基苯丙胺滥用治疗的需求是至关重要的。大麻素受体（CB1）拮抗剂减弱甲基苯丙胺自我给药和甲基苯丙胺诱导的啮齿动物行为致敏。因此，内源性大麻素传递是甲基苯丙胺滥用的潜在治疗靶点。尽管有强有力的行为证据，但很少有神经生理学数据证实CB1调节冰毒滥用。为了解决这个问题，提出了三个实验目的：目的1：确定冰毒精神运动激活的神经化学和电生理相关关系。我们假设甲基安非他明的激活在时间上与NAc中增强的亚秒多巴胺能传递和改变的电生理特征同时发生。在静脉注射冰毒期间，将记录自由运动大鼠伏隔核（NAc）自发的亚秒多巴胺释放、多个单单元活动和局部场电位，以验证这一假设。目的2：探讨利莫那班对甲基苯丙胺精神运动激活及其相关因素的影响。我们假设CB1拮抗剂/逆激动剂利莫那班可减弱甲基安非他明精神运动激活及其在NAc中的神经生理相关。用利莫那班或载体预处理的受试者将接受与目的1中描述的类似的实验设计，以支持这一假设。目的3：探讨利莫那班对NAc中冰毒精神运动致敏表达及其相关因素的影响。我们假设在致敏动物中，甲基安非他明激活的神经生理相关因素得到增强。我们进一步假设利莫那班会减弱这种增强的表达。对甲基苯丙胺致敏的动物将接受目标1和目标2中描述的类似实验方案，以验证这一假设。

DESCRIPTION (provided by applicant): In 2004 approximately 74,000 emergency room visits and over 150,000 hospital admissions were attributed to methamphetamine (METH) abuse. Accordingly, the need for effective METH abuse therapies is paramount. Cannabinoid receptor (CB1) antagonists attenuate both METH self-administration and METH- induced behavioral sensitization in rodents. Thus, endogenous cannabinoid transmission is a potential therapeutic target for METH abuse. Despite robust behavioral evidence, little neurophysiological data exist substantiating CB1 modulation of METH abuse. To address this, 3 experimental aims are proposed: Aim 1: To determine neurochemical and electrophysiological correlates of METH psychomotor activation. We hypothesize that METH activation is temporally coincident with both augmented, sub-second dopaminergic transmission and altered electrophysiological profiles in the NAc. Spontaneous, sub-second dopamine release, multiple single-unit activity and local field potentials will be recorded in the nucleus accumbens (NAc) of freely-moving rats during intravenous METH administration to validate this hypothesis. Aim 2: To determine the effect of rimonabant on METH psychomotor activation and its correlates in the NAc. We hypothesize that the CB1 antagonist/ inverse agonist rimonabant attenuates METH psychomotor activation and its neurophysiological correlates in the NAc. Subjects pretreated with either rimonabant or vehicle will be subjected to a similar experimental design as described in Aim 1 to support this hypothesis. Aim 3: To determine the effect of rimonabant on METH psychomotor sensitization expression and its correlates in the NAc. We hypothesize that the neurophysiological correlates of METH activation are enhanced in sensitized animals. We further hypothesize that rimonabant attenuates expression of this enhancement. Animals sensitized to METH will be subjected to similar experimental protocols as described in Aims 1 and 2 to validate this hypothesis.