Approved medications for alcohol use disorder (AUD) display modest effect sizes. Pharmacotherapy aimed at the mechanism(s) by which ethanol activates the dopamine reward pathway may offer improved outcomes. Basal and ethanol-induced accumbal dopamine release in the rat involve glycine receptors (GlyR) in the nucleus accumbens (nAc). Glycine transporter 1 (GlyT-1) inhibitors, which raise extracellular glycine levels, have repeatedly been shown to decrease ethanol intake in the rat. To further explore the rational for elevating glycine levels in the treatment of AUD, this study examined accumbal extracellular glycine and dopamine levels and voluntary ethanol intake and preference in the rat, after systemic treatment with glycine. The effects of three different doses of glycine i.p. on accumbal glycine and dopamine levels were examined using in vivo microdialysis in Wistar rats. In addition, the effects of the intermediate dose of glycine on voluntary ethanol intake and preference were examined in a limited access two-bottle ethanol/water model in the rat. Systemic glycine treatment increased accumbal glycine levels in a dose-related manner, whereas accumbal dopamine levels were elevated in a subpopulation of animals, defined as dopamine responders. Ethanol intake and preference decreased after systemic glycine treatment. These results give further support to the concept of elevating central glycine levels to reduce ethanol intake and indicate that targeting the glycinergic system may represent a pharmacologic treatment principle for AUD.

批准的治疗酒精使用障碍 (AUD) 的药物显示出适度的效果。针对乙醇激活多巴胺奖赏途径的机制的药物疗法可能会改善结果。大鼠中基础和乙醇诱导的伏隔多巴胺释放涉及伏隔核 (nAc) 中的甘氨酸受体 (GlyR)。甘氨酸转运蛋白 1 (GlyT-1) 抑制剂可提高细胞外甘氨酸水平，已多次被证明可以减少大鼠的乙醇摄入量。为了进一步探讨在 AUD 治疗中提高甘氨酸水平的合理性，本研究检查了甘氨酸全身治疗后大鼠的累积细胞外甘氨酸和多巴胺水平以及自愿乙醇摄入量和偏好。使用 Wistar 大鼠体内微透析检查三种不同剂量的甘氨酸腹膜内注射对累积甘氨酸和多巴胺水平的影响。此外，在大鼠的有限访问两瓶乙醇/水模型中检查了中等剂量的甘氨酸对自愿乙醇摄入和偏好的影响。全身甘氨酸治疗以剂量相关的方式增加累积甘氨酸水平，而在定义为多巴胺反应者的动物亚群中，累积多巴胺水平升高。全身甘氨酸治疗后，乙醇摄入量和偏好降低。这些结果进一步支持了提高中心甘氨酸水平以减少乙醇摄入量的概念，并表明针对甘氨酸能系统可能代表了 AUD 的药物治疗原则。