1. ¹Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
2. ²Alcohol Research Center (116-A), VA Connecticut Healthcare System, West Haven, CT, USA
3. ³Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA
4. ⁴Institute of Living, Hartford Hospital, Hartford, CT, USA
5. ⁵Section of Biostatistics, School of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA
6. ⁶Department of Psychiatry, University of North Carolina Medical School, Chapel Hill, NC, USA

Correspondence: Dr JH Krystal, Alcohol Research Center (116-A), Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Avenue, Park Street, West Haven CT 06516, USA, Tel: +203 937 4790, Fax: +203 937 3468; E-mail: john.krystal@yale.edu

Received 1 June 2005; Revised 5 August 2005; Accepted 7 September 2005; Published online 4 January 2006.

Abstract

The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.