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.
Repeated treatment with phencyclidine (PCP) over 14 days at 7.5 mg/kg per day significantly reduced the frequency of backpedalling, a serotonergic stereotyped behavior, indicating tolerance. This repeated treatment also decreased the equilibrium dissociation constant (Kd) of [3H]paroxetine binding to serotonin transporters in whole brain excluding the cerebellum, without changing the maximum number of binding sites (Bmax). A single PCP treatment did not alter binding parameters. The results suggest that repeated PCP treatment induces tolerance in serotonergic stereotyped behavior and increases the affinity of serotonin transporters, possibly as a compensatory response to chronic inhibition of serotonin uptake.