Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation

Abstract

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder.

Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus

“…Therefore, the lack of an effect of chronic nicotine on backward trace conditioned safety is consistent with our interpretation that acute nicotine facilitates a maladaptive hippocampus-dependent trace US–CS association. A caveat is that only a single dose of nicotine was tested, but this dose falls within a range of doses resulting in similar plasma nicotine and cotinine levels as observed in active human smokers (Cole et al, 2014; Hukkanen et al, 2005; Kutlu et al, 2016b). …”

Basolateral amygdala, nicotinic cholinergic receptors, and nicotine: Pharmacological effects and addiction in animal models and humans

“…In contrast, extinction of contextual fear conditioning is impaired by acute and chronic nicotine and during withdrawal (Kutlu, Oliver, Huang, Liu‐Chen, & Gould, ). This impairment is mediated by β 2 ‐containing nAChRs and associated with upregulation of nAChRs in hippocampus (Kutlu et al., ; Portugal, Kenney, & Gould, ). ABT‐089A, a partial agonist of α 4 β 2 ‐containing nAChRs, but not an α 7 agonist, reversed this well‐known withdrawal‐induced deficit in fear extinction (Yildirim, Connor, & Gould, ).…”

“…Studies in knock-out mice indicate that b 2 -containing nAChRs mediate these acute effects of nicotine (Davis & Gould, 2007; for review : Kutlu & Gould, 2015). In contrast, extinction of contextual fear conditioning is impaired by acute and chronic nicotine and during withdrawal (Kutlu, Oliver, Huang, Liu-Chen, & Gould, 2016). This impairment is mediated by b 2 -containing nAChRs and associated with upregulation of nAChRs in hippocampus (Kutlu et al, 2016;Portugal, Kenney, & Gould, 2008).…”

Sex differences in the effects of nicotine on contextual fear extinction

“…For acute and chronic nicotine extinction, a 2-way ANOVA (drug × extinction day) was conducted on normalized freezing levels (freezing × 100/initial freezing), wherein extinction day was treated as a repeated measure. Freezing was normalized to ensure differences in baseline freezing did not affect subsequent freezing curves (Tian et al, 2008; Kutlu et al, 2016b). Planned comparisons of extinction across doses were made using Bonferroni-corrected t-tests.…”

“…It has been shown that acute nicotine enhances contextual fear learning in male and female mice (Gould, 2003; Gould et al, 2004; Gould & Wehner, 1999). In male mice, acute nicotine has been shown to impair contextual fear extinction, stunting the normal decline of the fear response across extinction trials without affecting general freezing behavior (Kutlu & Gould, 2014; Kutlu et al, 2016a; 2017a,b) and enhance spontaneous recovery of extinguished contextual fear (Kutlu et al, 2016b). Chronic nicotine has similar effects on contextual fear learning process.…”