CB1 Modulation of Opioid Peptides and Ethanol Intake

CB1 对阿片肽和乙醇摄入量的调节

• 批准号: 7087921
• 负责人: LOREN H. PARSONS
• 金额: $ 33.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087921
• 关键词: alcoholic beverage consumption; amygdala; basal ganglia; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; cannabinoid receptor; dopamine; dosage; ethanol; gamma aminobutyrate; laboratory rat; microinjections; neurochemistry; opioid receptor; receptor expression; reinforcer; self medication; substance abuse related behavior

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.

大量证据暗示了大麻素系统在调解和/或 调节乙醇的行为作用。在此提出了阿片类肽链接 过程虽然特定阿片受体在CB1受体诱导的 尚不清楚乙醇饮用的调节。基于我们工作的最新数据和其他数据的数据，假设CB1受体对乙醇自我给药产生了积极的控制，并且这种影响部分是由CB1受体诱导的阿片类肽释放的调节所介导的。该提案中的项目旨在进一步表征大麻素操纵对乙醇消耗的影响，并评估MU，Delta和Kappa阿片受体（及其相关的内源性肽配体）在CB1受体乙醇摄入量中的相对参与。具体目标1将评估选择性阿片类受体拮抗剂逆转CB1激动剂诱导的乙醇自我给药的增加的能力。具体目标2将表征改变脑内源性大麻素神经传递对乙醇自我给药的影响，并将研究每类阿片类受体在这些作用中的影响。在这些实验中，将使用内源性大麻素再摄取和水解的抑制作用，以增加间质内源性大麻素水平，这在我们的实验室中发现以增加乙醇自我给药。具体的目标3将研究三个大脑区域中由大麻素和阿片类操纵产生的乙醇自我给药的改变：伏隔核，腹侧对段区域和杏仁核的中央核。在 这些实验将使用体内微透析，以提供阿片类肽释放的CB1受体调节的直接证据。最后，具体目标4将检查CB1受体操纵在乙醇复发模型中产生的影响，以评估CB1拮抗剂对酒精中毒治疗的潜在治疗效用。