Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats

Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity. We investigated the necessity of NMDArs for extinction of cocaine seeking and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci. Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal. Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, administration of the NMDAr coagonist D-serine after four brief extinction sessions attenuated lever pressing during subsequent extinction, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction. Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse.