Mouse model predicts effects of smoking and varenicline on event-related potentials in humans

Rudnick, Noam D.; Strasser, Andrew A.; Phillips, Jennifer M.; Jepson, Christopher; Patterson, Freda; Frey, Joseph M.; Turetsky, Bruce I.; Lerman, Caryn; Siegel, Steven J.

doi:10.1093/ntr/ntq049

Cited by 18 publications

(34 citation statements)

References 62 publications

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“…Whereas previous reports indicate a significant role of α4β2* nAChRs in varenicline’s mechanism of action (Rollema et al, 2009; Rudnick et al, 2010), our results suggest a possible role for α7* nAChRs in varenicline induced improvement of deficient P20-N40 inhibition, via modulation of the test amplitude, of DBA/2 mice. At 0.6 mg/kg, varenicline significantly decreased the test amplitude with no significant effect on the conditioning amplitude (Figure 1).…”

Section: Discussioncontrasting

confidence: 98%

“…Auditory evoked responses, as a measure of sensory processing, are proposed to be a pre-attentional aspect of early sensory processing (Rollema et al, 2009) or the habituation of the auditory evoked responses to repeated stimuli (Rudnick et al, 2010). In rats expressing normal auditory evoked responses, varenicline does not impact P20-N40 inhibition (Rollema et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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The smoking cessation drug varenicline improves deficient P20–N40 inhibition in DBA/2 mice

Wildeboer-Andrud

Stevens

2011

Pharmacology Biochemistry and Behavior

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Varenicline, an FDA approved smoking cessation pharmacotherapy, is an α4β2* nicotinic acetylcholine receptor (nAChR) partial agonist and an α7* nAChR full agonist. Both subtypes of nAChR are involved in modulating auditory evoked responses in rodents. In DBA/2 mice, an inbred strain, auditory evoked responses to paired auditory stimuli fail to inhibit to the second stimulus. This mouse strain replicates the auditory evoked response inhibition deficit experienced by the majority of schizophrenia patients. In this current study, we examined the effects of five different doses of varenicline (0.06, 0.3, 0.6, 3 and 6 mg/kg) on auditory evoked responses in anesthetized DBA/2 mice. We also examined α4β2* and α7* nAChR selective antagonist pre-administration prior to varenicline administration in order to determine the impact of these two nAChR subtypes in the effects produced by varenicline. Four of the five doses of varenicline produced improvements in auditory evoked response inhibition deficits. Selective blockade of either the α4β2* or α7* nAChR in competition with 0.6 mg/kg varenicline prevented varenicline induced improvements. In competition with a higher dose of varenicline (3 mg/kg) only blockade of the α4β2* nAChR prevented varenicline induced improvement in auditory evoked response inhibition. These data indicate the importance of α4β2* nAChRs and the potential involvement of the α7* subtype in varenicline’s effects on auditory evoked responses in DBA/2 mice.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The smoking cessation drug varenicline improves deficient P20–N40 inhibition in DBA/2 mice

Wildeboer-Andrud

Stevens

2011

Pharmacology Biochemistry and Behavior

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“…Despite differing opinions of the participants regarding the applicability of ERPs to this construct, ERPs were eventually rejected from inclusion in the battery owing to some members’ opinion that ERPs lack of specificity for the construct of gain control. More specifically, amplitude of the N1 (N100 in a human or N40 in a mouse) likely would be an excellent candidate due to the nearly perfect correspondence for parametric and pharmacological response properties between species, including gain control (Featherstone et al, 2012; Jutzeler et al, 2011; Maxwell et al, 2004a,b; Metzger et al, 2007; Rudnick et al, 2010; Siegel et al, 2005). Alternatively, P1 amplitude and gating deficits (as measured with P50 in humans and P20 in mice) have proven less reliable across both human and animal studies, reducing enthusiasm for this particular measure as a true endophenotype of schizophrenia or as a valid animal model for the disease (de Wilde et al, 2007a,b).…”

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confidence: 99%

Animal models and measures of perceptual processing in Schizophrenia

Siegel

Talpos

Geyer

2013

Neuroscience & Biobehavioral Reviews

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This paper summarizes the discussions regarding animal paradigms for assessing perception at the seventh meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS). A breakout group at the meeting addressed candidate tests in animals that might best parallel the human paradigms selected previously in the CNTRICS program to assess two constructs in the domain of perception: gain control and visual integration. The perception breakout group evaluated the degree to which each of the nominated tasks met pre-specified criteria: comparability of tasks across multiple species; construct validity; neuroanatomical homology between species; and dynamic range across parametric variation.

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“…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 increases in S 1 but not S 2 (Crawford et al, 2002;Cromwell and Woodward, 2007;Metzger et al, 2007;Phillips et al, 2004Phillips et al, , 2007Rudnick et al, 2010). Clozapine, the prototype of the 'atypical' antipsychotics, and one of the few medications shown to reverse auditory sensory gating impairment in both schizophrenia and animal models, appears to selectively reduce S 2 -P50 responsivity via an α7 nicotinic mechanism (Simosky et al, 2003;Adler et al, 2004;Nagamoto et al, 1996Nagamoto et al, , 1999.…”

Section: Cihr Author Manuscriptmentioning

confidence: 99%

“…reduced DA tone) would be associated with reduced S 1 -P50 and P50 gating, and that nicotine would increase S 1 -P50 and P50 gating in the presence of the 10R allele. As evidence of nicotine-altered P50/gating in tobacco abstinent smokers may be interpreted as a reversal of withdrawal-induced alterations in sensory processing (Rudnick et al, 2010), and not an absolute affect of nicotine per se, these hypotheses were investigated in nonsmokers. …”

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

et al. 2011

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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...

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Mouse model predicts effects of smoking and varenicline on event-related potentials in humans

Cited by 18 publications

References 62 publications

The smoking cessation drug varenicline improves deficient P20–N40 inhibition in DBA/2 mice

The smoking cessation drug varenicline improves deficient P20–N40 inhibition in DBA/2 mice

Animal models and measures of perceptual processing in Schizophrenia

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

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