The Contribution of Ionotropic GABAergic and N‑methyl‑D‑Aspartic Acid Receptors in the Antidepressant‑Like Effects of Hispidulin

Background: Salvia triloba, commonly known as sage belongs to Lamiaceae family, is conventionally used as a brain‑enhancing tonic. The purpose of this study was to evaluate hispidulin, a flavonoid isolated from S. triloba for its antidepressant‑like effects and to identify its possible mechanisms of action. Materials and Methods: Mouse models of the forced swimming test (FST) and tail‑suspension test (TST) were used to assess the antidepressant‑like effects of hispidulin. Results: The results showed that hispidulin at the doses level of 1–10 mg/kg, intraperitoneal (ip) exerted significant antidepressant‑like effects in both FST and TST. Pretreatment of animals with bicuculline (4 mg/kg, ip; a competitive γ‑aminobutyric acid (GABA) antagonist) and N‑methyl‑D‑aspartic acid (NMDA) (75 mg/kg, ip, glutamate receptor agonist) significantly blocked the reduction in immobility time of mice treated with hispidulin (3 mg/kg, ip) in FST. Furthermore, brain GABA levels were significantly decreased by coadministration of hispidulin with bicuculline, whereas glutamate levels were increased with combined administration of hispidulin and NMDA. Moreover, coadministration of sub‑effective doses of hispidulin (0.5 mg/kg, ip) and ketamine (0.3 mg/kg, ip) or MK 801 (0.1 mg/kg, ip) also exerted significant antidepressant‑like effects in FST. Conclusion: Taken together, these findings suggest that hispidulin possess significant antidepressant‑like effects mediated most likely through GABAergic and glutamatergic mechanisms.