Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
EBioMedicine. 2023 Jul;93:104642. doi: 10.1016/j.ebiom.2023.104642. Epub 2023 Jun 7.
Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.
In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.
In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.
Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.
Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.
胰高血糖素样肽 1 受体 (GLP-1R) 激动剂已被发现可减少啮齿动物和超重酒精使用障碍 (AUD) 患者的饮酒量。然而，低剂量司美格鲁肽（一种对 GLP-1R 具有更高效力和亲和力的激动剂）是否能够减弱啮齿动物的酒精相关反应以及潜在的神经元机制尚不清楚。
在间歇性访问模型中，我们检查了司美格鲁肽降低酒精摄入量和阻断类似复发的饮酒的能力，并对雄性和雌性大鼠的伏隔核 (NAc) 中荧光标记的司美格鲁肽结合进行了成像。在雄性小鼠中测试了司美格鲁肽对酒精诱导的运动刺激和 NAc 中多巴胺释放的抑制作用。我们评估了司美格鲁肽对雄性小鼠中多巴胺代谢物 (DOPAC 和 HVA) 的体内释放和代谢多巴胺的酶 (MAOA 和 COMT) 的基因表达的影响。
在雄性和雌性大鼠中，急性和重复给予司美格鲁肽可减少酒精摄入量并预防类似复发的饮酒。此外，在饮酒雄性和雌性大鼠的 NAc 中检测到荧光标记的司美格鲁肽。此外，司美格鲁肽减弱了酒精引起的过度运动和增加 NAc 中多巴胺的能力。进一步在雄性小鼠中显示，当酒精存在时，司美格鲁肽增加了 NAc 中的 DOPAC 和 HVA，并增加了 COMT 和 MAOA 的基因表达。
总之，这表明司美格鲁肽通过减少酒精诱导的奖赏和 NAc 依赖机制来减少饮酒行为。由于司美格鲁肽还降低了两性酒精饮用大鼠的体重，即将进行的临床研究应测试司美格鲁肽是否可降低超重 AUD 患者的饮酒量和体重的可能性。
瑞典研究委员会（2019-01676）、LUA/ALF（723941）来自萨尔格伦斯卡大学医院和瑞典脑基金会。
