Role of the NMDA receptor subunit in the expression of the discriminative stimulus effect induced by ketamine.

Ketamine, an NMDA receptor antagonist used as an anesthetic, can produce psychotomimetic effects like nightmares and hallucinations with chronic use. In Fischer 344 rats trained to discriminate ketamine (5 mg/kg) from saline, non-competitive NMDA receptor antagonists that block NR2A- and NR2B-containing receptors (phencyclidine, dizocilpine) and an NR2A-preferring antagonist (dextromethorphan) fully substituted for the ketamine cue in a dose-dependent manner. The NR2B-selective antagonist ifenprodil, the competitive NMDA antagonist CPP, and the sigma receptor ligand DTG did not generalize. The findings suggest that antagonism of NR1/NR2A-containing NMDA receptors may be critical for producing ketamine's discriminative stimulus effects.

Study at a glance

Abstract

Ketamine, which is a non-competitive NMDA receptor antagonist, has been used as a dissociative anesthetic agent. However, chronic use of ketamine produces psychotomimetic effects, such as nightmares, hallucination and delusion. Therefore, the present study was designed to ascertain the role of the NMDA receptor and sigma receptor in the discriminative stimulus effect induced by ketamine. Fischer 344 rats were trained to discriminate between ketamine (5 mg/kg, i.p.) and saline under a fixed-ratio 10 food-reinforced procedure. Non-competitive antagonists for both NR2A- and NR2B-containing NMDA receptors, such as phencyclidine (0.1--1 mg/kg, i.p.) and dizocilpine (3--30 microg/kg, i.p.), and the NR2A-containing NMDA receptor-preferred antagonist dextromethorphan (3--56 mg/kg, i.p.) fully substituted for the ketamine cue in a dose-dependent manner. By contrast, the NR2B-containing NMDA receptor antagonist ifenprodil (5--20 mg/kg, i.p.) exhibited no generalization. Additionally, the competitive NMDA antagonist 3-[(+/-)-2-carboxypiperazine-4-yl] propyl-1-phosphonic acid ((+/-)-CPP; 0.3--5.6 mg/kg, i.p.) and a sigma receptor ligand DTG (0.3--3 mg/kg, s.c.) displayed no generalization to the ketamine cue. These results suggest that NR1/NR2A subunit containing NMDA antagonism may be critical for the production of the ketamine cue.