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.

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.

A HPLC method for simultaneous determination of uridine, inosine, guanosine, adenosine and cordycepine
in Cordyceps sinensis was developed. The sample solution was prepared with 0.5% phosphoric acid solution by ultrasonic extraction. The separation was performed on a ZORBAX SB-AQ (150 mmí4.6 mm, 5 μm)column with gradient elution by 0.1% formic acid solution and acetonitrile, with column temperature 30℃, at a flow rate of 0.8 mL/min, and detected at wavelength of 260 nm. The result of method validation showed that the developed method had high accuracy and good repeatability. This method has been successfully applied for analysis of 5 kinds of nucleosides in different parts of C. sinensis. The results indicated that content of nucleosides in stroma is higher than that in insect body and whole C. sinensis.