The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

Abstract

Although schizophrenia has been considered primarily a disease of dopaminergic neurotransmission, the role of dopamine in auditory sensory gating deficits in this disorder and their amelioration by smoking/nicotine is unclear. Hypothesizing that individual differences in striatal dopamine levels may moderate auditory gating and its modulation by nicotine, this preliminary study used the mid-latency (P50) auditory event-related potential (ERP) to examine the single dose (6 mg) effects of nicotine (vs. placebo) gum on sensory gating in 24 healthy nonsmokers varying in the genetic expression of the dopamine transporter (DAT). Consistent with an inverted-U relationship between dopamine level and the drug effects, individuals carrying the 9R (lower gene expression) allele, which is related to greater striatal dopamine levels, tended to evidence increased baseline gating compared to 10R (higher gene expression) allele carriers and showed a reduction in gating with acute nicotine. The present results may help to understand the link between excessive smoking and sensory gating deficits in schizophrenia and to explain the potential functional implications of genetic disposition on nicotinic treatment in schizophrenia. Keywords schizophrenia; P50; gating; dopamine transporter gene; nicotine; smoking Early theoretical models of information processing in schizophrenia postulated impairment in the preattentive, automatic processing of sensory input to be a contributing factor in the appearance of psychotic symptoms, perceptual disturbances, and various cognitive deficits that characterize this disorder (Venables, 1964). Meta-analyses and reviews of event-related potential (ERP) studies probing auditory sensory gating in a paired stimulus paradigm (involving the presentation two [ CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptfound that ~90% of patients with schizophrenia as well as ~50% of their first-degree relatives exhibit insufficient inhibitory processing of repetitive, irrelevant acoustic stimuli (Bramon et al., 2004;De Wilde et al., 2007;Patterson et al., 2008). Typically assessed with the amplitude of the early (50 ms) positive ERP component, P50, abnormal auditory sensory gating has been evidenced by a relative inability to suppress P50 to S 2 , and is expressed by larger S 2 /S 1 ratio (rP50) and/or smaller S 1 minus S 2 difference (dP50) scores.Smoking and acute nicotine have transiently corrected deficient P50 processing in schizophrenia patients and their relatives, respectively (Adler et al., 1992(Adler et al., , 1993. In addition, in a rodent model of schizophrenia-like gating deficiency, studies assessing the P20-N40 ERP, which is an analogue of the human P50, have shown agonists and antagonists of the α7 nicotinic receptor to improve deficient S 2 inhibition and to block normal S 2 inhibition, respectively (Stevens et al., 1998(Stevens et al., , 1999Simosky et al., 2001). Other studies reporting gating improvements with nicotine in rodents and humans, however, have found increa...

Association of the Nicotinic Receptor α7 Subunit Gene (CHRNA7) with Schizophrenia and Visual Backward Masking

“…We postulated that the cholinergic system is one candidate of target enhancement which may be deficient in schizophrenic patients (32). These observations are in line with other studies which showed that the nicotinic system is involved in the regulation of visual information processing (33–36) including sensory gating and P50 suppression (9, 37). Interestingly, an alpha 7 receptor agonist improved both p50 gating function and cognition in schizophrenic patients (38).…”

Effects of COMT genotype on sensory gating and its modulation by nicotine: Differences in low and high P50 suppressors

“…Antipsychotics, which are primarily dopamine (DA) antagonists, exert little or no effects on cognitive deficits and gating in SZ (Adler et al, 2004), but individual differences in genotypes (DRD2, DAT1) regulating striatal DA (Knott et al, 2010b;Millar et al, 2011) have been shown to affect baseline and nicotine-modulated gating. The relationship between prefrontal DA and cognitive performance has also been described as a U-shaped curve, whereby an excess or an insufficiency can be detrimental (Goldman-Rakic et al, 2000;Williams-Gray et al, 2007;Monte-Silva et al, 2009).…”

Effects of acute nicotine on somatosensory change-related cortical responses

“…Indeed, enhancing effects of nicotine on MMN have been observed in patients with schizophrenia (Dulude et al, 2010). Conversely, the possibility that the phenotype (Fisher et al, 2012b) and genotype (Millar et al, 2011) of patients with schizophrenia influence nicotine's effects has been suggested. Further studies are needed to elucidate the factors affecting nicotine's effects on the automatic change-detecting system.…”