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

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.