Enhancement of neurogenesis and antidepressant-like efficacy through combined activation of Sigma-1 and 5-HT1A receptors: focus on Sigma-1-5-HT1A heteroreceptor complex.

Abstract

The sigma-1 receptor (S1R) attracts significant interests as a potential target for rapid-onset antidepressant-like effects, particularly due to its capacity to swiftly stimulate serotonergic neurons in the dorsal raphe nucleus (DRN). However, the precise regulatory mechanism involved remains unclear. Therefore, this study aims to examine the interaction between the selective S1R agonist, SA-4503 and 8-OH-DPAT, a serotonin1A (5-HT1A) receptor agonist, in mice with depressive-like behavior induced by chronic restraint stress (CRS). Preliminary investigations were conducted to explore the potential mechanisms underlying the accelerated antidepressant-like effect regulated by the combined activation of S1R and 5-HT1A receptors. The results showed that the coadministration of SA4503 (1.0 mg/kg, i.g.), a selective S1R agonist, and 8-OH-DPAT (0.3 mg/kg, i.g.) produces antidepressant-like effects. However, the doses of 8-OH-DPAT employed in this study lack intrinsic antidepressant-like activity in this model. Moreover, using an in-situ proximity ligation assay obtained the first evidence of S1R-5-HT1A heteroreceptor complexes in the midbrain DRN and dentate gyrus (DG) of the forebrain in mice. The formation of these heterocomplexes is influenced by pharmacological agents and is also closely associated with the development of depressive-like behaviors in mice. Mechanistically, combined treatment with S1R and 5-HT1A agonists showed a synergistic effect on neurogenesis and plasticity in the dorsal DG region of the hippocampus in CRS mice. Our findings significantly advanced our understanding of S1R-mediated neuroplasticity, suggesting new therapeutic strategies for developing rapid-acting antidepressants.