Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low-rate operant schedule.

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to produce rapid and lasting antidepressant effects in treatment-resistant patients with major depressive disorder and in preclinical behavioral assays. The present study sought to extend the preclinical antidepressant-like effects of ketamine using the differential-reinforcement-of-low-rate 72 s operant task in rats, as well as to determine whether the more selective and higher affinity NMDA receptor antagonist MK-801 produced antidepressant-like effects similar to those of ketamine. Ketamine, the NMDA receptor agonist N-methyl-D-aspartic acid, the tricyclic antidepressant imipramine, and the selective serotonin reuptake inhibitor fluoxetine all produced antidepressant-like effects by increasing the number of reinforcers, decreasing the number of responses, and producing a rightward shift in the peak location of the inter-response time distributions. Conversely, MK-801 and the dopamine receptor agonist D-amphetamine produced a psychostimulant-like effect by decreasing the number of reinforcers, increasing the number of responses, and producing a leftward shift in the peak location of the inter-response time distributions. Although a subeffective dose of ketamine attenuated the antidepressant-like effects of NMDA, a subeffective dose of NMDA did not alter the antidepressant-like effects of ketamine. These data indicate that ketamine and MK-801 produced dissociable effects in the differential-reinforcement-of-low-rate 72 s task, and further suggest that the underlying mechanisms responsible for the antidepressant effects of ketamine may be unique to ketamine and not shared by all NMDA receptor antagonists.