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

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nicotine & Tobacco Research (Impact Factor: 3.3). 06/2010; 12(6):589-97. DOI: 10.1093/ntr/ntq049
Source: PubMed


Nicotine alters auditory event-related potentials (ERPs) in rodents and humans and is an effective treatment for smoking cessation. Less is known about the effects of the partial nicotine agonist varenicline on ERPs.
We measured the effects of varenicline and nicotine on the mouse P20 and varenicline and smoking on the human P50 in a paired-click task. Eighteen mice were tested following nicotine, varenicline, and their combination. One hundred and fourteen current smokers enrolled in a placebo-controlled within-subject crossover study to test the effects of varenicline during smoking and abstinence. Thirty-two subjects participated in the ERP study, with half receiving placebo first and half varenicline first (VP).
Nicotine and varenicline enhanced mouse P20 amplitude, while nicotine improved P20 habituation by selectively increasing the first-click response. Similar to mice, abstinence reduced P50 habituation relative to smoking by reducing the first-click response. There was no effect of varenicline on P50 amplitude during abstinence across subjects. However, there was a significant effect of medication order on P50 amplitude during abstinence. Subjects in the PV group displayed reduced P50 during abstinence, which was blocked by varenicline. However, subjects in the VP group did not display abstinence-induced P50 reduction.
Data suggest that smoking improves sensory processing. Varenicline mimics amplitude changes associated with nicotine and smoking but fails to alter habituation. The effect of medication order suggests a possible carryover effect from the previous arm. This study supports the predictive validity of ERPs in mice as a marker of drug effects in human studies.

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Available from: Freda Patterson, Mar 25, 2014
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    • "Pharmacological and parametric manipulations have suggested a close correspondence between the rodent N40 and human N100 (Metzger et al. 2007; Amann et al. 2008; Swerdlow et al. 2012). For example, pharmacological manipulations using dopamine agonists and nicotinic cholinergic agonists in rodents produce alterations in N40 that closely overlap with the effects such drugs have on the human N100 (Siegel et al. 2005; Maxwell et al. 2006; Kanes et al. 2007; Metzger et al. 2007; Amann et al. 2010; Halene and Siegel 2008; Rudnick et al. 2009, 2010; Cao et al. 2012; Featherstone et al. 2012). As such, it is likely that the reduction in N40 amplitude observed here in BRAT rats is analogous to the N100 reductions observed in schizophrenia patients. "
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    • "Previously, the effect of varenicline on auditory evoked responses of C57BL/6 mice was determined to produce an overall increase in P20 amplitude in response to both the first and second auditory stimuli (Rudnick et al., 2010). This study examined only the peak response, P20, and not the entire P20-N40 waveform. "
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    • "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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