Endocannabinoids and cue-induced drug-seeking behavior

描述（由申请人提供）：最近的报告表明，选择性大麻素CB1受体拮抗剂SR141716A减弱了药物相关条件提示和药物引发注射恢复消失的药物寻求行为的能力。值得注意的是，SR141716A的这种作用在广泛的药物类别中观察到，包括精神兴奋剂、阿片类药物、尼古丁和乙醇。这种广泛的影响表明，内源性大麻素系统作为治疗复发的治疗靶点具有很大的潜力。然而，内源性大麻素调节复发行为的神经底物和神经药理学机制尚未得到表征，并且尚未显示在恢复熄灭的药物寻求行为期间改变的内源性大麻素信号传导的直接证据。因此，本项目的目标是评估内源性大麻素对条件线索诱导的海洛因寻求行为的影响，在复发的操作性反应-恢复模型。CB1受体通过其调节条件线索诱导的海洛因寻求行为的神经基质将使用选择性CB1受体拮抗剂，内源性大麻素再摄取的选择性抑制剂，和内源性大麻素物质（R）-methanandamide和2-arachidonoylglycerol的定点微量输注进行研究。要研究的大脑区域是基底外侧杏仁核、内侧前额叶皮质和丘脑核核心。将采用体内微透析采样来表征条件线索诱导的寻求药物行为恢复过程中这些脑区间质性内源性大麻素水平的变化，并将开始其他神经化学研究来表征内源性大麻素调节寻求药物行为的神经药理学机制。

DESCRIPTION (provided by applicant): Recent reports have demonstrated that the selective cannabinoid CB1 receptor antagonist SR141716A attenuates the ability of drug-associated conditioned cues and drug priming injections to reinstate extinguished drug-seeking behavior. Remarkably this effect of SR141716A has been observed across a wide range of drug classes including psychostimulants, opiates, nicotine and ethanol. This broad spectrum of influence suggests that the endocannabinoid system has great potential as a therapeutic target for the treatment of relapse. However, the neural substrates and neuropharmacological mechanisms through which endocannabinoids modulate relapse behavior have not been characterized, and direct evidence of altered endocannabinoid signaling during the reinstatement of extinguished drug-seeking behavior has not been shown. Thus, the goals of this project are to evaluate the influence of endocannabinoids on conditioned cue-induced heroin-seeking behavior in an operant response-reinstatement model of relapse. The neural substrates through which CB1 receptors modulate conditioned cue-induced heroin-seeking behavior will be investigated using site-directed microinfusions of a selective CB1 receptor antagonist, a selective inhibitor of endocannabinoid reuptake, and the endocannabinoid substances (R)-methanandamide and 2-arachidonoylglycerol. The brain regions to be investigated are the basolateral amygdala, the medial prefrontal cortex, and the nucleus accumbens core. In vivo microdialysis sampling will be employed to characterize alterations in interstitial endocannabinoid levels in these brain regions during conditioned cue-induced reinstatement of extinguished drug-seeking behavior, and additional neurochemcial studies will begin to characterize the neuropharmacological mechanisms through which endocannabinoids modulate drug-seeking behavior.