Pharmacological evidence for glutamatergic pathway involvement in the antidepressant-like effects of 2-phenyl-3-(phenylselanyl)benzofuran in male Swiss mice

Depression is a multifactorial and heterogeneous disease with several neurobiological mechanisms underlying its pathophysiology, including dysfunctional glutamatergic neurotransmission, which makes the exploration of the glutamate pathway an interesting strategy for developing novel rapid-acting antidepressant treatments. In the present study, we aimed to evaluate the possible glutamatergic pathway relation in the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF 1 ) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF 1 administration at effective (50 mg/kg) or subeffective (1 mg/kg) doses by intragastric route ( ig ). TST and the open-field test (OFT) were employed in all behavioral experiments. The pretreatment of mice with N-methyl-D-aspartate (NMDA) (0.1 pmol/site, intracerebroventricular, icv , a selective agonist of the NMDA receptors), D-serine (30 µg/site, icv , a co-agonist at the NMDA receptor), arcaine (1 mg/kg, intraperitoneal, ip , an antagonist of the polyamine-binding site at the NMDA receptor), and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (2,5 µg/site, icv , an antagonist of the AMPA/kainate type of glutamate receptors) inhibited the antidepressant-like effects of SeBZF 1 (50 mg/kg, ig ) in the TST. Coadministration of a subeffective dose of SeBZF 1 with low doses of MK-801 (0.001 mg/kg, ip , a non-competitive NMDA receptor antagonist) or ketamine (0.1 mg/kg, ip , a non-selective antagonist of the NMDA receptors) produced significant antidepressant-like effects (synergistic action). These findings suggest the involvement of the glutamatergic system, probably through modulation of ionotropic glutamate receptors, in the antidepressant-like action of SeBZF 1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects. Graphical Abstract