title: Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low-rate operant schedule.
abstract: 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.
authors.affiliation: Department of Psychology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Hillhouse
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Porter
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007099:Imipramine / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology
chemical_list: D000928:Antidepressive Agents; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D007099:Imipramine