Chronic administration of berberine attenuates depressive-like behavior in rats subjected to chronic unpredictable mild stress combined with ACTH treatment: Role of nitrergic system.

Major depressive disorder (MDD) remains a significant clinical concern because of its poor response to conventional antidepressants. Berberine, an isoquinoline alkaloid of natural origin has shown promising antidepressant-like effects in preclinical models. However, the mechanism by which berberine ameliorates depressive-like behavior has not been clearly studied. Herein, we examined the effect of berberine on depression induced by chronic unpredictable mild stress (CUMS) combined with adrenocorticotropic hormone (ACTH) treatment in rats and explored the role of the nitrergic system in its mechanism. The CUMS (42 days) with ACTH (14 days) -treated rats showed decreased sucrose preference, percentage of time spent in the central area of open field tests, exploration towards the novel object in the novel object recognition test, and increased immobility time in the forced swim test. There was increased neuronal nitric oxide synthase (nNOS) immunoreactivity in the paraventricular nucleus of hypothalamus (PVN), serum corticosterone level, and reduced dopamine and serotonin levels of the hippocampus in the CUMS + ACTH-treated rats. The chronic intraperitoneal (i.p.) administration of berberine (5 mg/kg; i.p.) for 14 days to the CUMS + ACTH-treated rats reversed all these parameters. Furthermore, the administration of sodium nitroprusside (SNP; 1 mg/kg) prior to the berberine treatment in CUMS + ACTH-treated rats blocked its positive effect. The findings suggest that berberine treatment may exert its antidepressant-like and memory-enhancing effects, at least in part, by attenuating hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, potentially through the involvement of nitrergic signaling.