title: Effects of COMT genotype on sensory gating and its modulation by nicotine: Differences in low and high P50 suppressors.
abstract: Elevated smoking rates seen in schizophrenia populations may be an attempt to correct neuropathologies associated with deficient nicotinic acetylcholine receptors and/or dopaminergic systems using exogenous nicotine. However, nicotine's effects on cognitive processing and sensory gating have been shown to be baseline-dependent. Evidence of a restorative effect on sensory gating deficits by nicotine-like agonists has been demonstrated, however, its underlying mechanisms in the context of dopamine dysregulation are unclear. Catechol-O-methyltransferase (COMT), a key dopamine regulator in the brain, contains a co-dominant allele in which a valine-to-methionine substitution causes variations in enzymatic activity leading to reduced synaptic dopamine levels in the Val/Val genotype. Using a randomized, double-blind, placebo-controlled design with 57 non-smokers, this study examined the effects of COMT genotype on sensory gating and its modulation by nicotine in low vs. high suppressors. The results were consistent with the hypothesis that increased dopamine resulting from nicotine stimulation or Met allelic activity would benefit gating in low suppressors and impair gating in high suppressors, and that this gating improvement with nicotine would be more evident in Val carriers who were low suppressors, while the gating impairment would be more evident in Met carriers who were high suppressors. These findings reaffirm the importance of baseline-dependency and suggest a subtle relationship between COMT genotype and baseline-stratified levels of sensory gating, which may help to explain the variability of cognitive abilities in schizophrenia populations.
authors.affiliation: University of Ottawa Institute of Mental Health Research, Royal Ottawa Mental Health Centre, Ottawa, ON, Canada K1Z 7K4.
authors.forename: S
authors.initials: S
authors.lastname: de la Salle
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Choueiry
authors.forename: D
authors.initials: D
authors.lastname: Impey
authors.forename: T
authors.initials: T
authors.lastname: Philippe
authors.forename: H
authors.initials: H
authors.lastname: Dort
authors.forename: A
authors.initials: A
authors.lastname: Millar
authors.forename: P
authors.initials: P
authors.lastname: Albert
authors.forename: V
authors.initials: V
authors.lastname: Knott
mesh_terms: D000293:Adolescent; D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004311:Double-Blind Method; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D055139:Sensory Gating / Q000187:drug effects* / Q000235:genetics*; D055815:Young Adult
chemical_list: D018722:Nicotinic Agonists; D009538:Nicotine; D002394:Catechol O-Methyltransferase
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