Increased serotonergic neurotransmission is not responsible for the anticompulsive effect of berberine in a murine model of obsessive-compulsive disorder

Berberine, an isoquinoline alkaloid, is being extensively explored in several clinical trials for the treatment of metabolic disorder and cancer. It is also reported to be a potent inhibitor of prolyl oligopeptidase, which makes it a potential candidate for the treatment of neuropsychiatric disorders. We have previously shown the potential of berberine in the control of seizures in various murine models of epilepsy, diabetes-induced memory dysfunction, and ethanol-induced hyperexcitability. We have now examined the effects of acute and subchronic (7 days) administration of berberine on a murine model of obsessive-compulsive disorder - the marble-burying behavior of male mice, because berberine administration is reported to increase brain monoamine levels - a desirable endpoint in the treatment of obsessive-compulsive disorder. The studies showed that an acute administration of berberine [1-25 mg/kg, intraperitoneally (i.p.)] dose-dependently inhibited marble burying in male mice without altering locomotor activity. This effect was retained after its subchronic administration. Furthermore, coadministration of a subeffective dose of berberine (1 mg/kg) and fluoxetine (5 mg/kg, i.p.) significantly reduced marble burying in mice. Pretreatment with p-chlorophenylamine (300 mg/kg, i.p. ×3 days), a tryptophan hydroxylase inhibitor and serotonin-depleting agent, completely blocked the effect of fluoxetine on marble burying, whereas it failed to alter the effect of berberine. In conclusion, the findings of the present investigation indicate that the anticompulsive and/or anxiolytic effect of berberine observed in the present investigation may be attributed to its effect on other neurotransmitter systems, such as the nitrergic or the dopaminergic system rather than to increased serotonin turnover in the brain.