Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment

Abstract

Glutamatergic mechanisms are implicated in psychiatric disorders such as schizophrenia. Modulation of glutamatergic neurotransmission via stimulation of the metabotropic glutamate 2/3 receptors (mGluR2/3) has been shown to reverse a number of behavioral effects of NMDA receptor antagonists thus indicating potential antipsychotic activity of mGluR2/3 agonists. The present study aimed to evaluate the effects of LY-354740 (mGluR2/3 agonist) and LY-487379 (mGluR2 potentiator) on social novelty discrimination in male Wistar rats that were treated with PCP (10 mg/kg, s.c.) on postnatal days 7, 9, and 11. During each test session (twice a week, postnatal days 70-100), an adult experimental rat was presented with a juvenile, untreated rat (4 weeks old) for a period of 30 min. At the end of this period, a second (novel) juvenile rat was introduced for 5 min. Adult rats spent more time exploring the novel than the familiar juvenile. This capacity for social novelty discrimination was impaired in rats that received neonatal PCP treatment and the impaired discrimination could be reversed by acute treatment with antipsychotic drugs such as clozapine (0.3-3 mg/kg) and the glycine transporter GlyT1 inhibitor SSR-504734 (1-10 mg/kg). Acute pretreatment with LY-354740 (1-10 mg/kg) or LY-487379 (3-30 mg/kg) facilitated social discrimination in rats with PCP administration history without having appreciable effects in controls and without affecting total time spent in social interaction. These results suggest that targeting glutamatergic functions may reverse long-term developmental cognitive deficits produced by PCP.