GLP-1RA induces time-dependent depression-like behaviors through neurotransmitter imbalance
10.3760/cma.j.cn311282-20250320-00148
- VernacularTitle:GLP-1RA通过神经递质失衡诱发时间依赖性抑郁样行为
- Author:
Lian LIU
1
;
Ke XU
;
Mintian ZHOU
;
Jia LIU
;
Feifei LIN
;
Fang FANG
Author Information
1. 上海交通大学医学院附属第一人民医院内分泌代谢科，上海 201620
- Publication Type:Journal Article
- Keywords:
Glucagon-like peptide-1 receptor agonist;
Depression-like behavior;
Neurotransmitters;
Hypothalamic-pituitary-adrenal axis;
Mouse model
- From:
Chinese Journal of Endocrinology and Metabolism
2025;41(8):664-671
- CountryChina
- Language:Chinese
-
Abstract:
Objective:This study aimed to investigate the effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs) on the emotional behaviors in wild-type mice and explore the underlying mechanisms.Methods:The study consisted of two parts.(1) Drug effect evaluation: C57BL/6 mice were randomly assigned to saline, semaglutide, or liraglutide groups. After 4 weeks of continuous subcutaneous administration, anxiety-like behaviors were evaluated by the open field tests and elevated plus maze, and depression-like behaviors were assessed by the forced swimming test and tail suspension test. Neurotransmitter levels, including NE, DA, 5-HT, GABA, and glutamate, were measured in target brain regions using LC-MS/MS. Hypothalamic activation subregions were identified by c-fos immunohistochemistry.(2) Time-course analysis: Mice received short-term administration(2 weeks), long-term administration(4 weeks), or drug withdrawal(assessed 4 weeks post-withdrawal). Behavioral performance, hypothalamic neurotransmitter levels, and plasma adrenocorticotropic hormone and corticosterone were measured.Results:Compared with the saline group, both GLP-1RAs significantly prolonged immobility time in the forced swimming and tail suspension tests. Multiple brain regions exhibited neurotransmitter abnormalities, including marked reductions in hypothalamic norepinephrine, dopamine, and γ-aminobutyric acid levels. Both GLP-1RAs significantly increased c-fos positive cell counts in the suprachiasmatic nucleus and arcuate nucleus of the hypothalamus. Time-course analysis revealed that short-term administration did not induce depressive phenotypes, whereas long-term administration led to depression-like behaviors, which recovered after drug withdrawal. Plasma adrenocorticotropic hormone and corticosterone levels were elevated even after short-term treatment and remained high after drug withdrawal, while hypothalamic neurotransmitter abnormalities normalized upon withdrawal.Conclusion:GLP-1RAs induce depression-like behaviors in a time-dependent manner, with neurotransmitter imbalance and persistent hyperactivation of the HPA axis likely contributing to the pathophysiological mechanism.
