RATIONALE: 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. OBJECTIVES: 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. METHODS: 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 (3.2-10.0 mg/kg) and MK-801 (0.032-0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2-20.0 mg/kg/day) and acute cocaine (10.0 mg/kg). RESULTS: Following acute administration, ketamine (3.2-10 mg/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 (0.032-0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS. CONCLUSIONS: 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.
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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 (3.2-10.0 mg/kg) and MK-801 (0.032-0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2-20.0 mg/kg/day) and acute cocaine (10.0 mg/kg). RESULTS: Following acute administration, ketamine (3.2-10 mg/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 (0.032-0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS. CONCLUSIONS: 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.
Authors: Gislaine Z Réus; Roberto B Stringari; Karine F Ribeiro; Ana K Ferraro; Marcelo F Vitto; Patrícia Cesconetto; Claúdio T Souza; João Quevedo Journal: Behav Brain Res Date: 2011-03-21 Impact factor: 3.332
Authors: S Stevens Negus; Ember M Morrissey; Marisa Rosenberg; K Cheng; Kenner C Rice Journal: Psychopharmacology (Berl) Date: 2010-01-26 Impact factor: 4.530
Authors: Farhana Sakloth; Elizabeth Leggett; Megan J Moerke; E Andrew Townsend; Matthew L Banks; S Stevens Negus Journal: Exp Clin Psychopharmacol Date: 2019-01-10 Impact factor: 3.157