Nicotine and smoker status moderate brain electric and mood activation induced by ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist V. Knott a,c, ⁎ , J. McIntosh a , A. Millar b , D. Fisher b , C. Villeneuve a , V. Ilivitsky c , E. Horn c a University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada b Department of Psychology/Behavioural Neuroscience, Carleton University, Ottawa, ON, Canada c Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada Received 6 April 2006; received in revised form 1 August 2006; accepted 9 August 2006 Available online 3 October 2006 Abstract As the increased smoking prevalence in schizophrenics may be interpreted as an adaptive response to an underlying biological defect, investigations into nicotine's actions within N-methyl-D-aspartate (NMDA) antagonist drug models of schizophrenia may improve our understanding of the role of glutamatergic neurotransmission in initiating and maintaining nicotine dependence in this disorder. In this double- blind, placebo-controlled, randomized study, the electroencephalographic (EEG) and subjective response to a sub-psychotomimetic intravenous dose of the NMDA antagonist ketamine was examined in 20 regular smokers and 20 non-smokers pretreated with placebo or nicotine gum. Although nicotine increased EEG arousal, ketamine produced electrocerebral signs of brain activation (decreased slow wave power) and sedation (decreased fast wave power and frequency), which were not affected by nicotine pretreatment and were evident only in non-smokers. Ketamine increased a number of self-report indices of subjective arousal, some of which were attenuated and potentiated by nicotine in smokers and non- smokers, respectively. These findings suggest that long-term (evidenced by smoker vs. non-smoker comparisons) and short-term (acute) nicotine exposure may alter NMDA receptor-mediated arousal and mood systems in a way that promotes nicotine dependence in smokers, and addresses neurobiological deficiencies in smokers with schizophrenia. © 2006 Elsevier Inc. All rights reserved. Keywords: Smokers; Non-smokers; Nicotine; Nicotine dependence; Glutamate; N-methyl-D-aspartate; Electroencephalography; Mood; Schizophrenia 1. Introduction Restrictive regulations and public education campaigns have dramatically diminished community rates of smoking from ∼ 60% to ∼ 25% over the past four decades. There is growing evidence, however, that smoking is becoming increasingly concentrated in highly dependent and vulnerable, at-risk popula- tions (Glassman, 1993) which over-include people of lower socio-economic status and individuals with other drug depen- dencies and/or behavioral or affective deficits amenable to management by nicotine (Pomerleau, 1997). Nicotine depen- dence (ND) is inordinately high in psychiatric patients, this population being the heaviest smokers and comprising ∼ 44% of the tobacco market (Lasser et al., 2000). There is a particularly high percentage of smokers (∼ 49–92%) in the schizophrenic (vs. mood disorder) population (de Leon and Diaz, 2005; Hughes et al., 1986) who, compared to non-patient smokers, perceive more benefits and find cigarettes more appealing than alternative rewards (Spring et al., 2003). Smoking has been shown to be a predictive factor in the onset of schizo- phrenia (Weiser et al., 2004) as well as a protective factor (Zammit et al., 2003), and has been shown to be heaviest in the more impaired schizophrenics (Apud et al., 2000) and for individuals currently receiving treatment (de Leon, 1996), which suggests that, in some cases, heavy smoking might be a form of self- medication of cognitive/affective deficits, and/or of neuroleptic Pharmacology, Biochemistry and Behavior 85 (2006) 228 – 242 www.elsevier.com/locate/pharmbiochembeh ⁎ Corresponding author. Clinical Neuroelectrophysiology and Cognitive Research Laboratory, University of Ottawa Institute of Mental Health Research, Royal Ottawa Hospital, 1145 Carling Avenue Ottawa, ON, Canada K1Z 7K4. Tel.: +1 613 722 6521x6847; fax: +1 613 722 5048. E-mail address: vknott@rohcg.on.ca (V. Knott). 0091-3057/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2006.08.005