Nicotine, Auditory Sensory Memory, and sustained Attention in a Human Ketamine Model of Schizophrenia: Moderating Influence of a Hallucinatory Trait

Verner Knott; Dhrasti Shah; Anne Millar; Judy McIntosh; Derek Fisher; Crystal Blais; Vadim Ilivitsky

doi:10.3389/fphar.2012.00172

Nicotine, Auditory Sensory Memory, and sustained Attention in a Human Ketamine Model of Schizophrenia: Moderating Influence of a Hallucinatory Trait

Front Pharmacol. 2012 Sep 28:3:172. doi: 10.3389/fphar.2012.00172. eCollection 2012.

Authors

Verner Knott¹, Dhrasti Shah, Anne Millar, Judy McIntosh, Derek Fisher, Crystal Blais, Vadim Ilivitsky

Affiliation

¹ Institute of Mental Health Research, University of Ottawa Ottawa, ON, Canada ; Neuroscience Program, Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada ; School of Psychology, University of Ottawa Ottawa, ON, Canada ; Institute of Cognitive Science, Carleton University Ottawa, ON, Canada ; Royal Ottawa Mental Health Centre Ottawa, ON, Canada.

Abstract

Background: The procognitive actions of the nicotinic acetylcholine receptor (nAChR) agonist nicotine are believed, in part, to motivate the excessive cigarette smoking in schizophrenia, a disorder associated with deficits in multiple cognitive domains, including low-level auditory sensory processes and higher-order attention-dependent operations.

Objectives: As N-methyl-d-aspartate receptor (NMDAR) hypofunction has been shown to contribute to these cognitive impairments, the primary aims of this healthy volunteer study were to: (a) to shed light on the separate and interactive roles of nAChR and NMDAR systems in the modulation of auditory sensory memory (and sustained attention), as indexed by the auditory event-related brain potential - mismatch negativity (MMN), and (b) to examine how these effects are moderated by a predisposition to auditory hallucinations/delusions (HD).

Methods: In a randomized, double-blind, placebo-controlled design involving a low intravenous dose of ketamine (0.04 mg/kg) and a 4 mg dose of nicotine gum, MMN, and performance on a rapid visual information processing (RVIP) task of sustained attention were examined in 24 healthy controls psychometrically stratified as being lower (L-HD, n = 12) or higher (H-HD) for HD propensity.

Results: Ketamine significantly slowed MMN, and reduced MMN in H-HD, with amplitude attenuation being blocked by the co-administration of nicotine. Nicotine significantly enhanced response speed [reaction time (RT)] and accuracy (increased % hits and d' and reduced false alarms) on the RVIP, with improved performance accuracy being prevented when nicotine was administered with ketamine. Both % hits and d', as well as RT were poorer in H-HD (vs. L-HD) and while hit rate and d' was increased by nicotine in H-HD, RT was slowed by ketamine in L-HD.

Conclusions: Nicotine alleviated ketamine-induced sensory memory impairment and improved attention, particularly in individuals prone to HD.

Keywords: N-methyl-d-aspartate receptor; attention; mismatch negativity; nicotine; nicotinic acetylcholine receptor; rapid visual information processing task; schizophrenia; sensory memory.