LAUSR

&NA; S 47445 is a positive modulator of glutamate AMPA‐type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro‐cognitive and anti‐stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.p.) with S 47445 were investigated on risk‐taking, motivational and cognitive behavior. S 47445 (1 and 10 mg/kg) increased the exploration of the elevated‐plus maze and light/dark box as well as the time spent grooming in the splash test, and improved social memory in PRS rats. Also, the effects of S 47445 were examined on the synaptic neurotransmission. The reduced depolarization‐evoked glutamate release induced by PRS was corrected with S 47445 (10 mg/kg). Remarkably, the reduction in glutamate release induced by PRS and corrected by S 47445 chronic treatment was correlated with all the behavioral changes. S 47445 at 10 mg/kg also normalized the lower levels of synaptic vesicle‐associated proteins in ventral hippocampus in PRS rats. Finally, S 47445 reversed the decrease of mGlu5 receptors, GR and OXTR induced by PRS. Collectively, in an animal model of stress‐related disorders, S 47445 corrected the imbalance between excitatory and inhibitory neurotransmission by regulating glutamate‐evoked release that is predictive of PRS behavioral alterations, and also normalized the reduction of trafficking of synaptic vesicles induced by PRS. These results support the interest of glutamatergic‐based therapeutic strategies to alleviate stress‐related disorders. HighlightsNeed to search for new antidepressants.Glutamate neurotransmission plays a new key role in psychopharmacology.PRS rats present dysfunctions in glutamate neurotransmission and related behaviors.S 47445 AMPAR potentiator corrects PRS induced behavioral/neurochemical alterations.Valid animal models should always be included in preclinical studies.