Withdrawal from chronic nicotine and subsequent sensitivity to nicotine challenge on contextual learning

Abstract

Nicotine withdrawal is associated with numerous symptoms including impaired hippocampus-dependent learning. Theories of nicotine withdrawal suggest that nicotinic acetylcholine receptors (nAChRs) are hypersensitive during withdrawal, which suggests enhanced sensitivity to nicotine challenge. Research indicates that prior exposure to nicotine enhances sensitivity to nicotine challenge, but it is unclear if this is due to prior nicotine exposure or specific to nicotine withdrawal. Therefore, the present experiments examined if prior nicotine exposure or nicotine withdrawal altered the effects of nicotine challenge on hippocampus-dependent learning. C57BL/6J mice were trained and tested in contextual conditioning following saline or nicotine challenge either during (24h after cessation) or after (14 days after cessation) a period of nicotine withdrawal symptoms. Nicotine challenge produced a greater enhancement of contextual conditioning relative to control withdrawal state in mice withdrawn from chronic nicotine for 24h compared to 14 days and corresponding saline controls. These experiments support the suggestion that during periods of abstinence, smokers may perceive tobacco providing a large boost in cognition.

Figure 1

Timeline of the experimental procedures. (A) Experiment 1: minipumps were implanted on day 0 and removed on day 12. Training and testing occurred on days 13 and 14, respectively. (B) Experiment 2: minipumps were implanted on day 0 and removed on day 12. Training and testing occurred on days 26 and 27, respectively.

Figure 2

Freezing data from both experiments for nicotine challenge treatment converted to percent change from control. The greatest relative enhancement of learning by nicotine challenge occurred in mice withdrawn from chronic nicotine for 24 hours. WCS = withdrawal from chronic saline. WCN = withdrawal from chronic nicotine. Error bars represent ± SEM. (*) indicates p < 0.05 compared to withdrawal groups within the same challenge dose.

Figure 3

The effects of nicotine challenge on contextual conditioning either (A) 24 hours (experiment 1) or (B) 14 days (experiment 2) after 12 days of chronic nicotine treatment. Nicotine challenge enhanced learning in animals withdrawn from chronic saline and chronic nicotine at both time points. WCS = withdrawal from chronic saline. WCN = withdrawal from chronic nicotine. Error bars represent ± SEM. (*) indicates p < 0.05 compared to WCS + saline mice within each time point. (#) indicates p < 0.05 compared to WCN + saline mice within each time point.