Abstract
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 (SeBZF1) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF1 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 SeBZF1 (50 mg/kg, ig) in the TST. Coadministration of a subeffective dose of SeBZF1 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 SeBZF1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects.
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The data supporting the findings of this study are obtainable from the corresponding author upon a reasonable request.
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Funding for this study was provided by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Finance Code 001), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant numbers 438384/2018–0 and 420386/2018–1). T.S.T.R. was a recipient of CAPES fellowship, as was the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, grant numbers 21/2551–0000728-1 and 21/2551–0000614-5). This study received support from UFPel's internal notice (PROAP – PRPPG) for textual review.
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CFB and CAB conceptualized, designed, and validated the study. These were also responsible for funding acquisition, project administration, supervision, and ethical approval. JSSN, GBB, and DA contributed to the work by synthesizing the compounds. TSTR, DSN, and LDK conducted the in vivo experiments. CFB and TSTR performed statistical analyses, interpreted the results, and wrote the manuscript; CAB revised it. All authors contributed to and have approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Rech, T.d., Strelow, D.N., Krüger, L.D. et al. Pharmacological evidence for glutamatergic pathway involvement in the antidepressant-like effects of 2-phenyl-3-(phenylselanyl)benzofuran in male Swiss mice. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3033–3044 (2023). https://doi.org/10.1007/s00210-023-02508-3
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DOI: https://doi.org/10.1007/s00210-023-02508-3