Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25‐6981, increases glutamate neurotransmission and induces antidepressant‐like effects

Abstract

Major depressive disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult‐born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N‐methyl‐D‐aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult‐born GCs for antidepressant‐like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B‐containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)‐(4‐hydroxyphenyl)‐(βS)‐methyl‐4‐(phenylmethyl)‐1‐piperidinepropanol (Ro25‐6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1 μg each side) following a chronic fluoxetine (18 mg/kg/day) treatment—known to increase adult hippocampal neurogenesis—in a mouse model of anxiety/depression. Responses in a neurogenesis‐dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and gamma‐aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid‐acting antidepressant‐like effect of local Ro25‐6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine‐independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.