CB1 Modulation of Opioid Peptides and Ethanol Intake

大量证据表明大麻素系统参与了介导和/或 调节乙醇的行为效应。阿片肽连接已被提出， 通过特定阿片受体的相对参与，CB 1受体诱导的 乙醇饮用的调节是未知的。根据我们的工作和其他人的最新数据，假设CB 1受体对乙醇自我给药产生积极的控制作用，这种影响部分由CB 1受体诱导的阿片肽释放调节介导。该提案中的项目旨在进一步表征大麻素操作对乙醇消耗的影响，并评估mu，delta和kappa阿片受体（及其相关的内源性肽配体）在CB 1受体调节乙醇摄入中的相对参与。具体目标1将评价选择性阿片受体拮抗剂逆转CB 1激动剂诱导的乙醇自我给药增加的能力。具体目标2将描述改变的脑内源性大麻素神经传递对乙醇自我给药的影响，并将研究各类阿片受体对这些影响的影响。在这些实验中，将分别使用内源性大麻素再摄取和水解的抑制来增加间质性内源性大麻素水平，这在我们的实验室中已经发现可以增加乙醇自我给药。具体目标3将研究大麻素和阿片类药物操作在三个脑区产生的乙醇自我给药的改变：杏仁核壳，腹侧被盖区和杏仁核中央核。在 将在这些实验中使用体内微透析来提供阿片肽释放的CB 1受体调节的直接证据。最后，具体目标4将检查CB 1受体操纵乙醇复发的动物模型中产生的影响，以评估CB 1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.