μ-阿片受体在乙醇和吗啡刺激长爪沙鼠中脑边缘多巴胺活性中的作用：乙醇的延迟效应。
μ-opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol.
机构信息
College of Pharmacy, Department of Pharmacology, University of Texas at Austin, 2409 University Avenue, Stop A1900, Austin, TX 78712-1113, USA.
出版信息
Psychopharmacology (Berl). 2013 Aug;228(3):389-400. doi: 10.1007/s00213-013-3041-9. Epub 2013 Mar 16.
RATIONALE
Naltrexone, a non-selective opioid antagonist, decreases the euphoria and positive subjective responses to alcohol in heavy drinkers. It has been proposed that the μ-opioid receptor plays a role in ethanol reinforcement through modulation of ethanol-stimulated mesolimbic dopamine release.
OBJECTIVES
To investigate the ability of naltrexone and β-funaltrexamine, an irreversible μ-opioid specific antagonist, to inhibit ethanol-stimulated and morphine-stimulated mesolimbic dopamine release, and to determine whether opioid receptors on mesolimbic neurons contribute to these mechanisms.
METHODS
Ethanol-naïve male Long Evans rats were given opioid receptor antagonists either intravenously, subcutaneously, or intracranially into the ventral tegmental area (VTA), followed by intravenous administration of ethanol or morphine. We measured extracellular dopamine in vivo using microdialysis probes inserted into the nucleus accumbens shell (n = 114).
RESULTS
Administration of naltrexone (intravenously) and β-funaltrexamine (subcutaneously), as well as intracranial injection of naltrexone into the VTA did not prevent the initiation of dopamine release by intravenous ethanol administration, but prevented it from being as prolonged. In contrast, morphine-stimulated mesolimbic dopamine release was effectively suppressed.
CONCLUSIONS
Our results provide novel evidence that there are two distinct mechanisms that mediate ethanol-stimulated mesolimbic dopamine release (an initial phase and a delayed phase), and that opioid receptor activation is required to maintain the delayed-phase dopamine release. Moreover, μ-opioid receptors account for this delayed-phase dopamine response, and the VTA is potentially the site of action of this mechanism. We conclude that μ-opioid receptors play different roles in the mechanisms of stimulation of mesolimbic dopamine activity by ethanol and morphine.
理由
纳曲酮是一种非选择性阿片受体拮抗剂，可减少重度饮酒者对酒精的欣快感和正面主观反应。据推测，μ-阿片受体通过调节乙醇刺激的中脑边缘多巴胺释放，在乙醇强化作用中发挥作用。
目的
研究纳曲酮和β-正丁啡烷，一种不可逆的μ-阿片受体特异性拮抗剂，抑制乙醇刺激和吗啡刺激的中脑边缘多巴胺释放的能力，并确定中脑边缘神经元上的阿片受体是否有助于这些机制。
方法
给予阿片受体拮抗剂的乙醇-naive 雄性 Long Evans 大鼠，通过静脉内、皮下或脑室内给予 VTA 中的纳曲酮，然后给予静脉内乙醇或吗啡。我们使用插入伏隔核壳（n = 114）的微透析探针在体内测量细胞外多巴胺。
结果
纳曲酮（静脉内）和β-正丁啡烷（皮下）的给药，以及纳曲酮颅内注射到 VTA 中，都不能防止静脉内给予乙醇引发多巴胺释放，但阻止了其延长。相比之下，吗啡刺激的中脑边缘多巴胺释放被有效抑制。
结论
我们的结果提供了新的证据，表明有两种不同的机制介导乙醇刺激的中脑边缘多巴胺释放（初始相和延迟相），并且阿片受体激活是维持延迟相多巴胺释放所必需的。此外，μ-阿片受体负责这种延迟相多巴胺反应，VTA 可能是这种机制的作用部位。我们得出结论，μ-阿片受体在乙醇和吗啡刺激中脑边缘多巴胺活动的机制中发挥不同的作用。
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