Antidepressant potential of agmatine: Effects on hypothalamic neurogenesis in rats with depressive behavior

This study aimed to investigate the behavioral, neuroendocrine, and hypothalamic molecular effects of agmatine in rats exposed to chronic mild stress (CMS). 28 adult male Wistar albino rats were randomly allocated to four groups: Control, CMS, CMS + Agmatine (CMS + A), and Agmatine (A) (n = 7/group). A repeated CMS schedule was applied to the CMS and CMS + A groups, and agmatine (10 mg/kg/day, i.p.) was administered once daily for 15 consecutive days beginning on day 9. Depression-related coping behavior was evaluated using the forced swimming test (FST), general locomotor activity using the open field test (OFT), and anxiety-like behavior using the elevated plus maze (EPM). Serum corticosterone levels and hypothalamic insulin-like growth factor 1 receptor (IGF1R), neuropeptide Y (NPY), and pro-opiomelanocortin (POMC) expression were also evaluated. In the FST, CMS-exposed rats showed decreased swimming and increased immobility over the experimental period, whereas CMS + A rats showed increased swimming and reduced immobility. Serum corticosterone levels were significantly higher in the CMS group than in the Control group and significantly lower in the CMS + A group than in the CMS group. The stress × treatment interaction for corticosterone was also significant. CMS did not produce a clear locomotor deficit or anxiety-like phenotype in the OFT or EPM. Hypothalamic IGF1R and NPY expression showed significant group-related changes associated with agmatine treatment, whereas POMC gene expression did not differ significantly among groups. POMC protein levels remained reduced in CMS and CMS + A animals. These findings suggest that agmatine exerts selective antidepressant-like and neuroendocrine effects under chronic stress conditions and may modulate hypothalamic IGF1R- and NPY related pathways.