Lei Kelly, Kwok Claudina, Darevsky David, Wegner Scott A, Yu JiHwan, Nakayama Lisa, Pedrozo Vincent, Anderson Lexy, Ghotra Shahbaj, Fouad Mary, Hopf Frederic W
Alcohol and Addiction Research Group, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States.
Front Neurosci. 2019 Feb 13;13:88. doi: 10.3389/fnins.2019.00088. eCollection 2019.
Excessive, binge alcohol drinking is a potent and pernicious obstacle to treating alcohol use disorder (AUD), and heavy-drinking humans are responsible for much of the substantial costs and harms of AUD. Thus, identifying key mechanisms that drive intake in higher-drinking individuals may provide important, translationally useful therapeutic interventions. Orexin-1-receptors (Ox1Rs) promote states of high motivation, and studies with systemic Ox1R inhibition suggest a particular role in individuals with higher intake levels. However, little has been known about circuits where Ox1Rs promote pathological intake, especially excessive alcohol consumption. We previously discovered that binge alcohol drinking requires Ox1Rs in medial nucleus accumbens shell (Shell), using two-bottle-choice Drinking-in-the-Dark (2bc-DID) in adult, male C57BL/6 mice. Here, we show that Shell Ox1Rs promoted intake during intermittent-access alcohol drinking as well as 2bc-DID, and that Shell inhibition with muscimol/baclofen also suppressed 2bc-DID intake. Importantly, with this large data set, we were able to demonstrate that Shell Ox1Rs and overall activity were particularly important for driving alcohol consumption in higher-drinking individuals, with little overall impact in moderate drinkers. Shell inhibition results were compared with control data combined from drug treatments that did not reduce intake, including NMDAR or PKC inhibition in Shell, Ox1R inhibition in accumbens core, and systemic inhibition of dopamine-1 receptors; these were used to understand whether more specific Shell Ox1R contributions in higher drinkers might simply result from intrinsic variability in mouse drinking. Ineffectiveness of Shell inhibition in moderate-drinkers was not due to a floor effect, since systemic baclofen reduced alcohol drinking regardless of basal intake levels, without altering concurrent water intake or saccharin consumption. Finally, alcohol intake in the first exposure predicted consumption levels weeks later, suggesting that intake level may be a stable trait in each individual. Together, our studies indicate that Shell Ox1Rs are critical mediators of binge alcohol intake in higher-drinking individuals, with little net contribution to alcohol drinking in more moderate bingers, and that targeting Ox1Rs may substantially reduce AUD-related harms.
过量暴饮酒精是治疗酒精使用障碍（AUD）的一个强大且有害的障碍，大量饮酒的人要为AUD造成的大部分巨大成本和危害负责。因此，确定驱动高饮酒量个体饮酒的关键机制可能会提供重要的、具有转化应用价值的治疗干预措施。食欲素-1受体（Ox1Rs）促进高动机状态，对全身Ox1R抑制的研究表明其在饮酒量较高的个体中发挥着特殊作用。然而，对于Ox1Rs促进病理性饮酒（尤其是过量饮酒）的神经回路却知之甚少。我们之前利用成年雄性C57BL/6小鼠的双瓶选择黑暗饮酒实验（2bc-DID）发现，暴饮酒精需要伏隔核壳内侧（壳部）的Ox1Rs。在此，我们表明，壳部的Ox1Rs在间歇性接触酒精饮酒以及2bc-DID实验中均促进饮酒，并且用蝇蕈醇/巴氯芬抑制壳部也能抑制2bc-DID实验中的饮酒量。重要的是，通过这个大数据集，我们能够证明壳部的Ox1Rs和整体活性对于驱动高饮酒量个体的酒精消费尤为重要，而对适度饮酒者的总体影响很小。将壳部抑制的结果与未降低饮酒量的药物治疗（包括壳部的NMDAR或PKC抑制、伏隔核核心的Ox1R抑制以及多巴胺-1受体的全身抑制）的对照数据进行比较；这些数据用于了解在高饮酒量个体中壳部更特异性的Ox1R作用是否可能仅仅是由于小鼠饮酒的内在变异性导致的。壳部抑制对适度饮酒者无效并非由于下限效应，因为全身给予巴氯芬可降低酒精摄入量，而与基础摄入量水平无关，同时不改变同时期的水摄入量或糖精消耗量。最后，首次接触时的酒精摄入量可预测数周后的饮酒水平，这表明饮酒量在每个个体中可能是一个稳定的特征。总之，我们的研究表明，壳部的Ox1Rs是高饮酒量个体暴饮酒精的关键介质，对饮酒量适中的个体的酒精摄入净贡献很小，并且靶向Ox1Rs可能会大幅减少与AUD相关的危害。
