Edvardsson Christian E, Cadeddu Davide, Ericson Mia, Adermark Louise, Jerlhag Elisabet
Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
EBioMedicine. 2025 May;115:105684. doi: 10.1016/j.ebiom.2025.105684. Epub 2025 Apr 17.
Alcohol use disorder (AUD) is a complex psychiatric condition with limited effective treatment options. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as potential AUD treatment, as they have been shown to modulate reward-related behaviours, including those linked to alcohol consumption. However, the underlying mechanisms and neurocircuitry remain unclear. This study investigated the role of GLP-1R in the lateral septum (LS), a brain region highly expressing GLP-1R and implicated in reward-related behaviours, including alcohol-induced reward and consumption.
Behavioural, neurochemical, molecular, and electrophysiological methods were used to investigate the effect of LS GLP-1R signalling in alcohol-mediated responses in rodents.
LS GLP-1R activation attenuated alcohol's rewarding effects, reducing locomotor stimulation, place preference, and accumbal dopamine release. Intra-LS infusion of the GLP-1R agonist exendin-4 (Ex4) reduced alcohol intake dose-dependently without affecting food or water consumption, while GLP-1R inhibition increased alcohol intake. Furthermore, LS GLP-1R expression correlated with alcohol intake in male but not female rats, suggesting sex-specific effects of long-term alcohol exposure. Ex vivo electrophysiology indicated that GLP-1R activation depressed LS neurotransmission via a gamma-aminobutyric acid (GABA) receptor-dependent mechanism.
This study provides new insights into how GLP-1R agonists may reduce alcohol intake. Overall, the findings underscore the potentially inhibitory neuromodulatory role of LS GLP-1R in regulating alcohol consumption through the modulation of dopaminergic reward processes tentatively involving GABA transmission.
Swedish Research Council (2023-2600), Sahlgrenska University HospitalLUA/ALF (grant no. 723941), Adlerbertska Research Foundation and Professor Bror Gadelius Foundation.
酒精使用障碍（AUD）是一种复杂的精神疾病，有效治疗选择有限。胰高血糖素样肽-1受体（GLP-1R）激动剂已成为潜在的AUD治疗药物，因为它们已被证明可调节与奖赏相关的行为，包括与饮酒相关的行为。然而，其潜在机制和神经回路仍不清楚。本研究调查了GLP-1R在外侧隔核（LS）中的作用，LS是一个高表达GLP-1R且与奖赏相关行为有关的脑区，包括酒精诱导的奖赏和饮酒行为。
采用行为学、神经化学、分子生物学和电生理学方法，研究LS中GLP-1R信号传导对啮齿动物酒精介导反应的影响。
激活LS中的GLP-1R可减弱酒精的奖赏效应，减少运动刺激、位置偏爱和伏隔核多巴胺释放。向LS内注射GLP-1R激动剂艾塞那肽-4（Ex4）可剂量依赖性地减少酒精摄入量，而不影响食物或水的消耗，而抑制GLP-1R则会增加酒精摄入量。此外，雄性大鼠而非雌性大鼠的LS中GLP-1R表达与酒精摄入量相关，提示长期酒精暴露存在性别特异性影响。离体电生理学研究表明，激活GLP-1R可通过γ-氨基丁酸（GABA）受体依赖性机制抑制LS神经传递。
本研究为GLP-1R激动剂如何减少酒精摄入量提供了新见解。总体而言，研究结果强调了LS中GLP-1R在通过调节多巴胺能奖赏过程（可能涉及GABA传递）来调节酒精消耗方面潜在的抑制性神经调节作用。
瑞典研究理事会（2023 - 2600）、萨尔格伦斯卡大学医院LUA/ALF（资助编号723941）、阿德勒贝茨卡研究基金会和布罗尔·加德柳斯教授基金会。
