The positive allosteric modulator at mGlu2 receptors, LY487379, reverses the effects of chronic stress-induced behavioral maladaptation and synaptic dysfunction in the adulthood

Chronic stress induces maladaptive neural responses in several brain areas including hippocampus. It has been demonstrated that chronic stress exposure induced a downregulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors, which would reduce the negative feedback role exerted by these receptors. The reduced availability of these receptors would enhance glutamate overflow in the hippocampus, supporting the hypothesis that hippocampal glutamatergic neurotransmission plays a key etiopathological determinant in stress-induced neuropsychiatric disorders. Since modulation of glutamatergic neurotransmission has been shown to represent an interesting pharmacological tool to treat psychiatric disorders, in the present study we have investigated the effects of the mGlu2 receptor positive allosteric modulator (PAM) LY487379. The rational bases of our study were: (a) chronic restraint stress (CRS) application in C57/BALB6 mouse induced a loss of resilience at the behavioral, biochemical, and electrophysiological level; (b) a superimposed familiar stressor (restraint) but not unfamiliar (i.e., forced swim stress) completely reversed the effects of CRS. Using the CRS model, in the present study we have investigated the effects of LY487379, an mGlu2 PAM, as well as a superimposed familiar stressor (acute restraint stress-ARS), on the immobility time at the tail suspension test and electrophysiological profile of glutamatergic transmission in the dentate gyrus (DG).