Role of N-methyl-D-aspartate receptors in the long-term effects of repeated social defeat stress on the rewarding and psychomotor properties of cocaine in mice

Abstract

Exposure to social stress increases the vulnerability of experimental animals to the rewarding effects of cocaine and it has been suggested that the glutamatergic system could be involved in these effects of stress. The aim of this work is to determine the role of N-methyl-d-aspartate (NMDA) glutamate receptors in the influence of social stress on the conditioned place preference and locomotor sensitization induced by cocaine. Mice treated with saline or NMDA antagonist memantine (5 or 10 mg/kg) underwent repeated social defeat or were kept in the exploration control condition. After three weeks, all groups (SAL + RSD, M5 + RSD, M10 + RSD, SAL + EXP, M5 + EXP and M10 + EXP) were conditioned with 1 mg/kg of cocaine (experiment 1). After nine weeks, each group was subdivided into two groups: one received saline and the other cocaine (25 mg/kg) on 3 consecutive days. After a 5-day interval, all the animals received a challenge of cocaine (10 mg/kg) and their locomotor activity was registered (experiment 2). Only stressed animals developed place preference, an effect prevented by the low dose of memantine. Control defeated mice (but not those treated with memantine) showed greater activity than mice not exposed to stress. Our results show that glutamate NMDA receptors are involved in the higher vulnerability to cocaine effects provoked by exposure to social defeat. They also suggest that memantine could be a useful therapeutic tool for treatment of cocaine dependent individuals exposed to stress conditions.

Keywords: Cocaine; Conditioned place preference; N-methyl-D-aspartate receptors; Repeated social defeat; Sensitization.