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

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Figure 1.

Grand averages of mouse (A) and human (B) event-related potentials showing the responses to S1 (black) and S2 (gray). Maximum positive deflections in (A) and (B) represent the P20 and P50 components, respectively. Dotted lines indicate stimulus onset and arrows indicate P20 and P50 components.

Figure 2.

Effects of nicotine and varenicline on the mouse P20. (A) Nicotine enhances P20 habituation by selectively increasing the response to S1. Amplitudes are averaged across varenicline conditions. This means that nicotine increases the S1 response of the P20 regardless of varenicline condition. (B) There was a main effect of varenicline, regardless of nicotine condition (nicotine or saline) or stimulus condition (S1 and S2). Varenicline increases P20 amplitude. Amplitudes are averaged across nicotine and stimulus conditions (S1 and S2). Data are presented as mean ± SEM, and collapsed across variables for which no statistically significant interaction effects were found. *p < .050 (Fisher’s LSD post hoc test).

Figure 3.

Effects of smoking and varenicline on human P50. (A) Smoking enhances P50 habituation by selectively increasing the response to S1. Amplitudes are averaged across varenicline conditions. This shows the main effect of smoking when collapsing across other variables. (B) Drug treatments were counterbalanced across study phases. Group 1 received varenicline during Phase 1 and placebo during Phase 2, while Group 2 received placebo during Phase 1 and varenicline during Phase 2. Group 1 did not show any changes in P50 amplitude across drug conditions, but Group 2 exhibited reduced P50 amplitude during abstinence on placebo. Amplitudes are averaged across S1 and S2 because there was no statistical interaction that included stimulus condition. Data are presented as mean ± SEM, and collapsed across variables for which no statistically significant interaction effects were found. *p < .050 (Fisher’s LSD post hoc test).