CB1 Modulation of Opioid Peptides and Ethanol Intake

大量证据表明大麻素系统参与了调解和/或 乙醇对行为影响的调节。在这项研究中提出了阿片肽的联系 特异性阿片受体相对参与CB1受体诱导的过程 酒精饮酒的调节方式尚不清楚。根据我们和其他人最近的研究数据，假设CB1受体对乙醇自身给药起正向控制作用，这种影响部分是通过CB1受体诱导的阿片肽释放调节来介导的。该提案中的项目旨在进一步表征大麻素操纵对酒精消耗的影响，并评估Mu、Delta和Kappa阿片受体(及其相关的内源性多肽配体)在CB1受体调节酒精摄取中的相对参与。具体目标1将评估选择性阿片受体拮抗剂逆转CB1激动剂诱导的乙醇自我给药增加的能力。具体目标2将表征改变的脑内大麻类神经传递对乙醇自我给药的影响，并将调查每类阿片受体在这些影响中的影响。在这些实验中，抑制内源性大麻素的再摄取和水解将分别用于增加间质内源性大麻素的水平，这是我们实验室发现的，可以增加乙醇的自我给药。具体目标3将研究大麻素和阿片类药物操作在三个大脑区域产生的乙醇自我给药的变化：伏隔核外壳、腹侧被盖区和杏仁中央核。在……里面 体内微透析将用于这些实验，以提供CB1受体调节阿片肽释放的直接证据。最后，特定目标4将在酒精复发的动物模型中检查CB1受体操作所产生的影响，以努力评估CB1拮抗剂治疗酒精中毒的潜在治疗效用。

A considerable amount of evidence implicates the cannabinoid system in the mediation and/or modulation of the behavioral effects of ethanol. An opioid peptide link has been suggested in this process though the relative involvement of specific opioid receptors in the CB1 receptor-induced modulation of ethanol drinking is not known. Based on recent data from our work and from others it is hypothesized that CB1 receptors exert a positive control over ethanol self-administration, and that this influence is mediated in part by a CB1 receptor-induced regulation of opioid peptide release. The projects in this proposal are designed to further characterize the effects of cannabinoid manipulations on ethanol consumption, and to evaluate the relative involvement of mu, delta and kappa opioid receptors (and their associated endogenous peptide ligands) in the modulation of ethanol intake by CB1 receptors. Specific Aim 1 will evaluate the ability of selective opioid receptor antagonists to reverse CB1 agonist-induced increases in ethanol self-administration. Specific Aim 2 will characterize the effects of altered brain endocannabinoid neurotransmission on ethanol self-administration, and will investigate the influence of each class of opioid receptor in these effects. Inhibition of endocannabinoid reuptake and hydrolysis, respectively, will be used in these experiments to increase interstitial endocannabinoid levels, which has been found in our laboratory to increase ethanol self-administration. Specific Aim 3 will investigate alterations in ethanol self-administration produced by cannabinoid and opioid manipulations in three brain regions: the nucleus accumbens shell, the ventral tegmental area and the central nucleus of the amygdala. In vivo microdialysis will be used in these experiments to provide direct evidence for a CB1 receptor modulation of opioid peptide release. Finally, Specific Aim 4 will examine the effects produced by CB1 receptor manipulations in an animal model of ethanol relapse in an effort to evaluate the potential therapeutic utility of CB1 antagonists for the treatment of alcoholism.