Atomoxetine reverses nicotine withdrawal-associated deficits in contextual fear conditioning - PubMed (original) (raw)

Atomoxetine reverses nicotine withdrawal-associated deficits in contextual fear conditioning

Jennifer A Davis et al. Neuropsychopharmacology. 2007 Sep.

Abstract

Recent evidence suggests that the cognitive symptoms of nicotine withdrawal and the cognitive symptoms of attention deficit hyperactivity disorder (ADHD) may share neural correlates. Thus, therapeutics that ameliorate ADHD symptoms may also ameliorate nicotine-withdrawal symptoms. The present research tested this hypothesis in an animal model of nicotine withdrawal-associated cognitive deficits using atomoxetine, a norepinephrine reuptake inhibitor that is approved by the FDA to treat the symptoms of ADHD. C57BL/6 mice were prepared with osmotic minipumps that administered 6.3 mg/kg/day of nicotine or saline, and the minipumps were removed after 12 days of continuous treatment. Twenty-four hours later, mice were trained in delay fear conditioning using two paired presentations of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus. Testing for freezing in response to the training context and for freezing in response to the CS occurred the next day. Nicotine-withdrawn mice and their saline-treated counterparts received either saline or atomoxetine before training and the context test. Consistent with previous research, the results indicate that mice withdrawn from chronic nicotine demonstrated lower levels of contextual fear conditioning than mice that were not withdrawn from chronic nicotine. Atomoxetine dose-dependently reversed the deficit, suggesting that nicotine withdrawal may be associated with changes in noradrenergic function, acetylcholinergic function, and/or with changes in cell signaling cascades that are activated by both nicotine and norepinephrine. These data suggest that atomoxetine may be efficacious for treating nicotine withdrawal-associated cognitive deficits that promote relapse in abstinent smokers.

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Figures

Figure 1

The effects of withdrawal from chronic nicotine and atomoxetine administration on contextual and auditory fear conditioning were examined. Tukey-adjusted post hoc analyses revealed that mice that were withdrawn from nicotine and received saline before training and testing (WCN + sal) demonstrated significantly lower levels of freezing in response to the context than mice withdrawn from chronic saline that received saline before training and testing (WCS + Sal). Atomoxetine (WCN + 2.0 Atom) administration reversed this deficit. There were no differences among groups in freezing in response to the CS. Nor were there significant pairwise differences between groups in baseline, immediate, or pre-CS freezing. Error bars represent±SE from the mean. *p <0.05 compared to mice withdrawn from chronic nicotine that received saline before training and testing (WCN + sal), n = 9–10 per group.

Figure 2

A second experiment was conducted to determine if a lower dose of atomoxetine would reverse nicotine withdrawal-associated deficits in contextual fear conditioning and to replicate our finding with the 2.0 mg/kg dose of atomoxetine. Tukey-adjusted follow-up comparisons revealed that 2.0 mg/kg (WCN + 2.0 Atom) but not 0.2 mg/kg (WCN + 0.2 Atom) of atomoxetine reversed the nicotine withdrawal-associated deficit in contextual fear conditioning. There were no differences among groups in baseline, immediate, pre-CS, and CS freezing. Error bars represent ±SE from the mean. *p<0.05 compared to mice withdrawn from chronic nicotine that received saline before training and testing (WCN + sal), n = 9–10 per group.

Figure 3

Experiment 3 examined if atomoxetine administration before training only or testing only would reverse nicotine withdrawal-associated deficits in contextual fear conditioning. A one-way ANOVA revealed that there was an effect of treatment. Tukey-adjusted follow-up comparisons indicate that mice withdrawn from chronic nicotine were impaired in contextual fear conditioning (WCN; Sal–Sal) compared to mice withdrawn from chronic saline that received saline at training and testing (WCS; Sal–Sal). Atomoxetine administration prior to testing only (WCN; Sal–Atom) but not training only (WCN; Atom–Sal) reversed this deficit. Error bars represent±SE from the mean. *p<0.05 compared to mice withdrawn from chronic nicotine that received saline before training and testing, n = 10–13 per group.

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Atomoxetine reverses nicotine withdrawal-associated deficits in contextual fear conditioning - PubMed (original) (raw)