NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking

Rationale Cocaine strengthens behaviors associated with its administration. The stress response by individuals that are defeated in a brief aggressive confrontation can also promote enduring behavioral consequences similar to those of stimulants. Objectives The study intends to find whether intermittent episodes of defeat promote cocaine's reinforcing effects by triggering N-methyl-D-aspartic acid (NMDA)-receptor-mediated plasticity in the ventral tegmental area (VTA). Materials and methods Long-Evans rats were investigated after four social defeats in three experiments. Two experiments examined systemic or intra-VTA antagonism of NMDA receptors during stress on the later expression of behavioral sensitization and cocaine self-administration during fixed and progressive ratio (PR) schedules of reinforcement (0.3 mg/kg/infusion), including a novel 24-h variable-dose continuous access binge (0.2, 0.4, and 0.8 mg/kg/infusion, delivered in an irregular sequence). Third, the expression of receptor proteins NR1 (NMDA) and GluR1 [alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)] were examined in VTA and nucleus accumbens. Results Intermittent defeats augment locomotor responses to cocaine and increase cocaine taking. Rates of responding during binges are increased after defeat stress. These effects are prevented when NMDA or AMPA receptor antagonists are administered before defeats. VTA infusions of the NMDA antagonist AP-5 (5 nmol/side) before stress prevents locomotor sensitization to cocaine and intensified responding for cocaine during a PR schedule or binge. Episodic defeats increase GluR1 AMPA subunit protein expression in the VTA. Conclusions Social stress stimulates NMDA receptors in the VTA, and this neural action of defeat may be essential for prompting a later increase in cocaine intake during binges.