Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U-964, CNRS UMR-7104, Université de Strasbourg, France.
Douglas Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Canada.
Addict Biol. 2019 Jan;24(1):28-39. doi: 10.1111/adb.12576. Epub 2017 Nov 2.
Mu opioid receptors (MORs) are widely distributed throughout brain reward circuits and their role in drug and social reward is well established. Substantial evidence has implicated MOR and the endogenous opioid system in alcohol reward, but circuit mechanisms of MOR-mediated alcohol reward and intake behavior remain elusive, and have not been investigated by genetic approaches. We recently created conditional knockout (KO) mice targeting the Oprm1 gene in GABAergic forebrain neurons. These mice (Dlx-MOR KO) show a major MOR deletion in the striatum, whereas receptors in midbrain (including the Ventral Tegmental Area or VTA) and hindbrain are intact. Here, we compared alcohol-drinking behavior and rewarding effects in total (MOR KO) and conditional KO mice. Concordant with our previous work, MOR KO mice drank less alcohol in continuous and intermittent two-bottle choice protocols. Remarkably, Dlx-MOR KO mice showed reduced drinking similar to MOR KO mice, demonstrating that MOR in the forebrain is responsible for the observed phenotype. Further, alcohol-induced conditioned place preference was detected in control but not MOR KO mice, indicating that MOR is essential for alcohol reward and again, Dlx-MOR KO recapitulated the MOR KO phenotype. Taste preference and blood alcohol levels were otherwise unchanged in mutant lines. Together, our data demonstrate that MOR expressed in forebrain GABAergic neurons is essential for alcohol reward-driven behaviors, including drinking and place conditioning. Challenging the prevailing VTA-centric hypothesis, this study reveals another mechanism of MOR-mediated alcohol reward and consumption, which does not necessarily require local VTA MORs but rather engages striatal MOR-dependent mechanisms.
μ 阿片受体 (MORs) 广泛分布于大脑奖励回路中，其在药物和社交奖励中的作用已得到充分证实。大量证据表明 MOR 和内源性阿片系统参与了酒精奖励，但 MOR 介导的酒精奖励和摄入行为的回路机制仍不清楚，也尚未通过遗传方法进行研究。我们最近在 GABA 能前脑神经元中创建了靶向 Oprm1 基因的条件性敲除 (KO) 小鼠。这些小鼠 (Dlx-MOR KO) 在纹状体中表现出主要的 MOR 缺失，而中脑 (包括腹侧被盖区或 VTA) 和后脑中的受体则完整无损。在这里，我们比较了总 MOR KO 和条件性 KO 小鼠的酒精饮用量和奖赏效应。与我们之前的工作一致，MOR KO 小鼠在连续和间歇性双瓶选择方案中饮酒量较少。值得注意的是，Dlx-MOR KO 小鼠的饮酒量减少与 MOR KO 小鼠相似，表明前脑中的 MOR 负责观察到的表型。此外，在对照小鼠中检测到酒精诱导的条件性位置偏好，但在 MOR KO 小鼠中未检测到，表明 MOR 是酒精奖励所必需的，而且 Dlx-MOR KO 再次重现了 MOR KO 表型。突变系的味觉偏好和血液酒精水平则没有变化。总之，我们的数据表明，在前脑 GABA 能神经元中表达的 MOR 对于酒精奖赏驱动的行为，包括饮酒和位置条件作用是必不可少的。这项研究挑战了普遍的 VTA 中心假说，揭示了另一种 MOR 介导的酒精奖赏和消费机制，该机制不一定需要局部 VTA MOR，而是需要涉及纹状体 MOR 依赖性机制。
