Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Neuropharmacology. 2019 May 1;149:124-132. doi: 10.1016/j.neuropharm.2019.02.020. Epub 2019 Feb 14.
The ability of glucagon-like peptide-1 (GLP-1) to reduce food intake involves activation of GLP-1 receptors (GLP-1R) in the nucleus of the solitary tract (NTS). It has also been demonstrated that systemic administration of GLP-1R agonists attenuates alcohol-mediated behaviors via, to date, unknown mechanisms. Therefore, we evaluated the effects of NTS-GLP-1R activation by exendin-4 (Ex4) on alcohol-induced locomotor stimulation, accumbal dopamine release and memory of alcohol reward in the conditioned place preference (CPP) model in mice. Moreover, the ability of Ex4 infusion into the NTS on alcohol intake was explored in rats. Ex4 into the NTS inhibits the acute effects of alcohol as measured by alcohol-induced locomotor stimulation, accumbal dopamine release and the memory consolidation of alcohol reward in the CPP paradigm. In addition, NTS-Ex4 dose-dependently decreases alcohol intake in rats consuming alcohol for 12 weeks. Pharmacological suppression of GLP-1R in the NTS prevents the ability of systemic Ex4 to block the alcohol-induced locomotor stimulation in mice. These data add a functional role of GLP-1R within the NTS, involving alcohol-related behaviors. In addition, they may provide insight into the GLP-1R containing brain areas that modulate the ability of GLP-1R agonists to reduce alcohol reinforcement. Collectively, this further supports GLP-1R as potential treatment targets for alcohol use disorder.
胰高血糖素样肽-1 (GLP-1) 降低食物摄入的能力涉及到孤束核 (NTS) 中 GLP-1 受体 (GLP-1R) 的激活。目前已经证明，GLP-1R 激动剂的全身给药通过迄今为止未知的机制减轻酒精介导的行为。因此，我们评估了 NTS-GLP-1R 激活对 exendin-4 (Ex4) 在小鼠条件性位置偏好 (CPP) 模型中对酒精诱导的运动刺激、伏隔核多巴胺释放和酒精奖赏记忆的影响。此外，还在大鼠中探索了 Ex4 输注到 NTS 对酒精摄入的影响。Ex4 输注到 NTS 抑制了酒精的急性作用，如酒精诱导的运动刺激、伏隔核多巴胺释放和 CPP 范式中酒精奖赏的记忆巩固所测量的。此外，NTS-Ex4 剂量依赖性地减少了 12 周内饮酒大鼠的酒精摄入量。NTS 中 GLP-1R 的药理学抑制阻止了系统给予 Ex4 阻断小鼠酒精诱导的运动刺激的能力。这些数据增加了 NTS 中 GLP-1R 的功能作用，涉及与酒精相关的行为。此外，它们可能为调节 GLP-1R 激动剂减少酒精强化能力的 GLP-1R 包含脑区提供了深入了解。总的来说，这进一步支持 GLP-1R 作为治疗酒精使用障碍的潜在治疗靶点。
