Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

Abstract

The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern. This study examined abuse-related effects of ketamine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison. Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency-rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2-10.0mg/kg) and MK-801 (0.032-0.32mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2-20.0mg/kg/day) and acute cocaine (10.0mg/kg). Following acute administration, ketamine (3.2-10mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032-0.32mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0mg/kg cocaine facilitated ICSS. The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.