Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice

Abstract

Nicotine withdrawal is associated with multiple symptoms such as anxiety, increased appetite, and disrupted cognition in humans. Although animal models have provided insights into the somatic and affective symptoms of nicotine withdrawal, less research has focused on the effects of nicotine withdrawal on cognition. Therefore, in this study, C57BL/6J mice were used to test the effects of withdrawal from chronic nicotine on foreground and background contextual fear conditioning, which present the context as a primary or secondary stimulus, respectively. Mice withdrawn from 12 days of chronic nicotine (6.3mg/kg/day) or saline were trained and tested in either foreground or background contextual fear conditioning; nicotine withdrawal-associated deficits in contextual fear conditioning were observed in both conditions. Mice were also tested for the effects of withdrawal on pre-pulse inhibition of the acoustic startle reflex (PPI), a measure of sensory gating, and on the acoustic startle reflex. Mice withdrawn from 12 days of chronic nicotine (6.3 or 12.6 mg/kg/day) or saline underwent one 30-min PPI and startle session; no effect of withdrawal from chronic nicotine on PPI or startle was observed for either dose at 24h after nicotine removal. Therefore, mice were tested at different time points following withdrawal from 12.6 mg/kg/day chronic nicotine (8, 24, and 48 h after nicotine removal). No effect of withdrawal from chronic nicotine was observed at any time point for PPI. Overall, these results demonstrate that nicotine withdrawal disrupts two methods of contextual learning but not sensory gating in C57BL/6J mice.

Figure 1

Fear conditioning results. Twenty-four hours of withdrawal from 6.3 mg/kg/day chronic nicotine produced deficits in freezing to the context when the context was either a foreground (A) and background (B) stimuli. There was no baseline freezing in any groups (Data not shown). Data are shown as mean ± SEM. *= p < 0.05. Foreground: Saline N =15, Nicotine N =13; Background: N =14 for both groups.

Figure 2

Dose-response analysis for withdrawal from chronic nicotine on PPI. There were no significant effects of 24 hours of withdrawal from chronic administration of 6.3 or 12.6 mg/kg/day nicotine on PPI. Data are shown as mean ± SEM. Saline N =14, 6.3 mg/kg/day nicotine N = 14, 12.6 kg/mg/day nicotine. N= 10.

Figure 3

Time-response analysis for withdrawal from chronic nicotine on PPI. There were no significant effects of withdrawal from chronic administration of the 12.6 mg/kg/day dose of nicotine on PPI measured at A) 8 hours B) 24 hours or C) 48 hours post withdrawal. Data are shown as mean ± SEM. N = 16 for all groups.

Figure 4

Dose-response analysis for withdrawal from chronic nicotine on the acoustic startle response. There were no significant effects of 24 hours of withdrawal from chronic administration of 6.3 or 12.6 mg/kg/day nicotine on startle. Data are shown as mean ± SEM reported in San Diego Instruments’ units reflecting maximum voltage change (V MAX). Saline N =14, 6.3 mg/kg/day nicotine N = 14, 12.6 kg/mg/day nicotine. N= 10.

Figure 5

Time-response analysis for withdrawal from chronic nicotine on the acoustic startle response. There were no significant effects of withdrawal from chronic administration of 12.6 mg/kg of nicotine on startle measured at A) 8 hours, B) 24 hours or C) 48 hours post withdrawal. Data are shown as mean ± SEM reported in San Diego Instruments’ units reflecting maximum voltage change (V MAX). N = 16 for all groups.