Endocannabinoid modulation of methamphetamine sensitization.

描述（由申请人提供）：2004年，约74，000次急诊室就诊和150，000多次住院治疗归因于甲基苯丙胺（METH）滥用。因此，对有效的METH滥用治疗的需求是至关重要的。大麻素受体（CB 1）拮抗剂减弱METH自我给药和METH诱导的啮齿动物行为敏化。因此，内源性大麻素传递是METH滥用的潜在治疗靶点。尽管有强有力的行为证据，但几乎没有神经生理学数据证实CB 1对METH滥用的调节。为了解决这个问题，提出了3个实验目标：目标1：确定METH精神激活的神经化学和电生理相关性。我们假设METH激活与NAc中增强的亚秒多巴胺能传递和改变的电生理特征在时间上一致。在静脉注射METH期间，将在自由移动大鼠的延髓核（NAc）中记录自发的亚秒多巴胺释放、多个单单位活动和局部场电位，以验证这一假设。目的2：确定利莫那班对NAc中METH精神兴奋及其相关因素的影响。我们假设CB 1拮抗剂/反向激动剂利莫那班减弱了NAc中的METH精神活动及其神经生理学相关性。用利莫那班或溶媒预处理的受试者将接受与目的1中所述相似的实验设计，以支持该假设。目的3：探讨利莫那班对NAc中METH精神敏感性表达及其相关因素的影响。我们假设METH激活的神经生理学相关性在致敏动物中增强。我们进一步假设利莫那班减弱了这种增强的表达。对METH致敏的动物进行与目的1和2中所述相似的实验方案，以验证该假设。

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.