Olney Jeffrey J, Navarro Montserrat, Thiele Todd E
Department of Psychology & Neuroscience, University of North Carolina, Chapel Hill, North Carolina.
Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
Alcohol Clin Exp Res. 2017 Mar;41(3):551-561. doi: 10.1111/acer.13336. Epub 2017 Feb 9.
Recent reports have demonstrated that binge-like ethanol (EtOH) drinking leads to an increase in hypothalamic orexin (OX) signaling and that suppressing this signaling via systemic administration of an orexin receptor (OXR) antagonist blocks this behavior; however, the specific OX pathways that modulate this behavior remain unknown. The goal of this study was to further elucidate the role of the OX system in binge-like EtOH drinking using behavioral, molecular, and pharmacological techniques.
The drinking-in-the-dark (DID) paradigm was used to model binge-like drinking behavior in male C57BL/6J mice. Experiment 1 examined changes in the OX precursor, prepro-orexin, within the hypothalamus following multiple cycle EtOH or sucrose DID using polymerase chain reaction (PCR) analysis. In experiments 2a and 2b, we used site-directed infusion of an OXR antagonist to examine the individual contribution of each OXR subtype within the ventral tegmental area (VTA) and central nucleus of the amygdala (CeA), respectively, in binge-like EtOH or sucrose drinking.
Findings from our PCR study revealed that multiple cycles of binge-like EtOH drinking did not lead to changes in prepro-orexin mRNA as a function of binge-like EtOH drinking. However, data from site-directed pharmacology studies indicate that the orexin-1 receptor (OX1R) is the predominate receptor subtype within the VTA and CeA that regulates binge-like EtOH drinking. Interestingly, inhibition of OX1Rs did not affect binge-like sucrose intake, which suggests that these OX circuits are specific for EtOH consumption.
As a whole, these data suggest that the VTA and CeA are important regions in which OX regulates binge-like EtOH drinking behavior. Moreover, these findings identify OXR antagonists as a potential treatment option that may be used to ameliorate problematic drinking behavior while leaving responding to natural rewards relatively intact.
最近的报告表明，暴饮样乙醇（EtOH）摄入会导致下丘脑食欲素（OX）信号增加，并且通过全身给予食欲素受体（OXR）拮抗剂抑制该信号可阻断这种行为；然而，调节这种行为的具体OX途径仍不清楚。本研究的目的是使用行为学、分子学和药理学技术进一步阐明OX系统在暴饮样EtOH摄入中的作用。
采用黑暗中饮水（DID）范式对雄性C57BL/6J小鼠的暴饮样饮酒行为进行建模。实验1使用聚合酶链反应（PCR）分析，研究多次循环EtOH或蔗糖DID后下丘脑内OX前体前食欲素原的变化。在实验2a和2b中，我们分别通过定点注射OXR拮抗剂，研究腹侧被盖区（VTA）和杏仁核中央核（CeA）中各OXR亚型在暴饮样EtOH或蔗糖摄入中的单独作用。
我们的PCR研究结果显示，多次循环的暴饮样EtOH摄入并未导致前食欲素原mRNA随暴饮样EtOH摄入而发生变化。然而，定点药理学研究数据表明，食欲素-1受体（OX1R）是VTA和CeA中调节暴饮样EtOH摄入的主要受体亚型。有趣的是，抑制OX1R并不影响暴饮样蔗糖摄入，这表明这些OX回路对EtOH摄入具有特异性。
总体而言，这些数据表明VTA和CeA是OX调节暴饮样EtOH饮酒行为的重要区域。此外，这些发现表明OXR拮抗剂可能是一种潜在的治疗选择，可用于改善有问题的饮酒行为，同时使对自然奖励的反应相对保持完整。
