Berberine‐Induced Behavioral Effects on Tail Suspension Test, BDNF, and CREB Levels in the Prefrontal Cortex, Hippocampus, and Amygdala: Modulation by Central Serotonergic Transmission

ABSTRACT Berberine has demonstrated an antidepressant‐like effect in rodents. Moreover, it increases central 5‐hydroxytryptamine (5‐HT)/brain‐derived neurotrophic factor (BDNF) or cyclic AMP response element binding protein (CREB) levels, but the exact role of these targets in its effect is still ill‐explained. Therefore, the present study explored the role of 5‐HT in berberine‐induced antidepressant‐like activity and BDNF or CREB expression in the specific brain regions. Administration of berberine (2, 5, and 20 mg/kg, i.p.) significantly reduced the duration of immobility of mice in the tail suspension test (TST) model without affecting locomotor activity, confirming its antidepressant‐like potential. Preinjection with the 5‐HT precursor, 5‐hydroxytryptophan (5‐HTP; 50 and 100 µg/mouse, intracerebroventricular [i.c.v.]), and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 and 10 mg/kg, i.p.), enhanced the berberine‐induced antidepressant‐like effect, whereas it was reversed in mice pretreated with 5‐HT 1A receptor agonist, 8‐hydroxy‐2(‐dipropylamino)tetralinhydrobromide (8‐OH‐DPAT) (0.01 and 0.1 µg/mouse, i.c.v.), or the 5‐HT 2A/2C receptor antagonist, mianserin (1, 1.5 µg/mouse, i.c.v.). Furthermore, berberine‐induced antidepressant‐like effects were significantly reduced in mice with depleted central 5‐HT, achieved by preinjection of the serotonin depletor, p ‐chlorophenylalanine ( p ‐CPA; 300 mg/kg, i.p. × 3 days). Additionally, berberine (20 mg/kg, i.p.) treatment significantly elevated BDNF expression in the whole brain, prefrontal cortex (PFC), and hippocampus and increased CREB expression in the whole brain and hippocampus only. Notably, berberine‐induced elevated BDNF expression in the whole brain and hippocampus was further enhanced in mice pretreated with 5‐HTP, fluoxetine, or 8‐OH‐DPAT, whereas mianserin or p ‐CPA reversed it. However, 5‐HTP enhanced and fluoxetine or 8‐OH‐DPAT did not alter, whereas mianserin or p ‐CPA reversed the berberine‐induced heightened BDNF expression in the PFC. On the other hand, berberine significantly increased CREB expression in the whole brain, which was further potentiated in mice pretreated with 5‐HTP, fluoxetine, 8‐OH‐DPAT, or mianserin, whereas it was reversed by p ‐CPA. However, berberine‐induced heightened CREB expression in the hippocampus was enhanced only in mice pretreated with 5‐HTP and attenuated by preinjection of mianserin or p ‐CPA. These findings suggest that serotonergic transmission modulates the antidepressant‐like activity and the BDNF/CREB alterations induced by berberine, likely through a mechanism mediated by 5‐HT 1A and 5‐HT 2A/2C receptors. This study underscores the role of serotonergic transmission in the effects induced by berberine.