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/6 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 Mice withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline were trained and tested in either foreground or background contextual fear conditioning; nicotine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 Mice withdrawn from 12 days of chronic nicotine (6.3 or 12.6 mg/kg/day) or saline underwent one 30-minute PPI and startle session; no effect of withdrawal from chronic nicotine on PPI or startle was observed for either dose at 24 hours 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 hours 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/6 mice.

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…It is important to note that these plasma nicotine levels were within the range observed in smokers [5,64]. Additionally, withdrawal from chronic nicotine disrupts contextual but not cued conditioning [2,33,30,132,133], and this impairment in contextual learning can be ameliorated by nicotine replacement and by the smoking cessation drugs bupropion and varenicline [30,132,135]. Together, these data suggest that associations between stimuli and the effects of nicotine in humans may contribute to nicotine addiction, and these effects can be modeled in mice by studying the effects of nicotine on contextual learning.…”

Donepezil reverses nicotine withdrawal-induced deficits in contextual fear conditioning in c57bl/6j mice.

“…Our lab has previously demonstrated that withdrawal from chronic nicotine produces deficits in contextual learning (André et al, 2008; Davis, James, Siegel, & Gould, 2005; Gould et al, 2012; Portugal & Gould, 2009; Wilkinson & Gould, 2013; Wilkinson, Turner, Blendy, & Gould, 2013). In addition, we have found that galantamine (an AChE inhibitor and positive allosteric modulator of α4β2 nAChRs) can reverse deficits in contextual learning produced by withdrawal from chronic nicotine (Wilkinson & Gould, 2011).…”

Nicotine Addiction and Psychiatric Disorders

“…While the enhancing effects of acute nicotine are well documented, several studies have shown that while chronic nicotine has no effect on fear conditioning, withdrawal from chronic nicotine impairs contextual and trace fear conditioning (André, Gulick, Portugal, & Gould, 2008; Davis, James, Siegel, & Gould, 2005; Portugal & Gould, 2009; Portugal, Wilkinson, Kenney, Sullivan, & Gould, 2012; Raybuck & Gould, 2009). There is also evidence suggesting that during chronic nicotine administration, hippocampal nAChRs desensitize and upregulate and the resulting hypersensitive cholinergic system may be responsible for the effects of nicotine withdrawal on hippocampus-dependent learning (Dani & Heinemann, 1996; Gould et al, 2012; Marks, Grady, & Collins, 1993; Wilkinson & Gould, 2013).…”