Endocannabinoid modulation of methamphetamine sensitization.

说明(申请人提供)：2004年，约有74,000人次的急诊室就诊和超过150,000人次的住院是由于滥用甲基苯丙胺(冰毒)。因此，对有效的冰毒滥用疗法的需求是至关重要的。大麻素受体(CB1)拮抗剂可减弱冰毒自身给药和冰毒诱导的啮齿动物行为敏感化。因此，内源性大麻素传递是治疗冰毒滥用的潜在靶点。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CB1对冰毒滥用的调节。为了解决这一问题，提出了3个实验目标：目标1：确定冰毒精神运动激活的神经化学和电生理相关性。我们假设冰毒的激活在时间上与NAC中增强的亚秒多巴胺能传递和改变的电生理特征是一致的。在静脉注射冰毒的过程中，自由活动大鼠的伏隔核(NAC)将记录到自发的亚秒多巴胺释放、多个单位活动和局部场电位，以验证这一假说。目的：探讨利莫那班对NAC中冰毒精神运动激活的影响及其相关因素。我们假设CB1拮抗剂/反向激动剂利莫那班减弱NAC中的甲基苯丙氨酸精神运动激活及其神经生理学关系。接受利莫那班或赋形剂预处理的受试者将接受与目标1中描述的相似的实验设计，以支持这一假设。目的：探讨利莫那班对NAC中冰毒运动敏化表达的影响及其相关因素。我们假设冰毒激活的神经生理学关联在致敏动物中增强。我们进一步假设，利莫那班减弱了这种增强的表达。对冰毒敏感的动物将接受类似的实验方案，如目标1和2中所述，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.