Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program (NIDA IRP) and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (NIAAA DICBR), NIH, Baltimore and Bethesda, Maryland, USA.
Neurobiology of Addiction Section, NIDA IRP, NIH, Baltimore, Maryland, USA.
JCI Insight. 2023 Jun 22;8(12):e170671. doi: 10.1172/jci.insight.170671.
Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.
越来越多的证据表明，胰高血糖素样肽-1（GLP-1）系统参与成瘾行为的神经生物学，GLP-1 类似物可能用于治疗酒精使用障碍（AUD）。在这里，我们研究了长效 GLP-1 类似物司美格鲁肽对啮齿动物酒精使用的生物行为相关性的影响。我们使用暗箱饮酒程序来测试司美格鲁肽对雄性和雌性小鼠 binge-like 饮酒的影响。我们还测试了司美格鲁肽对雄性和雌性大鼠 binge-like 和依赖诱导性饮酒的影响，以及司美格鲁肽对中枢杏仁核（CeA）和下丘脑前皮质（ILC）神经元的自发性抑制性突触后电流（sIPSCs）的急性影响。司美格鲁肽剂量依赖性地减少了小鼠的 binge-like 饮酒；对其他热量/非热量溶液的摄入也有类似的影响。司美格鲁肽还减少了大鼠的 binge-like 和依赖诱导性饮酒。司美格鲁肽增加了来自酒精-naive 大鼠的 CeA 和 ILC 神经元中的 sIPSC 频率，表明 GABA 释放增强，但对酒精依赖大鼠的 GABA 传递没有总体影响。总之，GLP-1 类似物司美格鲁肽减少了不同饮酒模型和物种的酒精摄入量，并调节了中枢 GABA 神经传递，为将司美格鲁肽作为 AUD 的一种潜在新型药物治疗进行临床测试提供了支持。
