Atomoxetine Reverses Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning

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 Nicotine-withdrawn mice and their saline-treated counterparts received either saline or atomoxetine before training and the context test. Consistent with previous research, the results indicate that mice withdrawn from chronic nicotine demonstrated lower levels of contextual fear conditioning than mice that were not withdrawn from chronic nicotine.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, acetycholinergic 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 withdrawalassociated cognitive deficits that promote relapse in abstinent smokers.

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.…”

“…Mice withdrawn from nicotine spend less time on the open arms relative to saline controls, indicating increased anxiety [28,77]. Furthermore, nicotine withdrawal-related deficits in contextual learning have been evaluated in mice [33,30,132,133]. Withdrawal-related decreases in the brain reward system in humans has been modeled using the intracranial self stimulation (ICSS) procedure, in which rats press a lever to deliver electrical stimulation to reward-related brain areas.…”

“…Acute nicotine enhances hippocampus-dependent forms of learning, such as trace cued conditioning [56,54] and contextual conditioning [34,57], whereas withdrawal from chronic nicotine produces deficits in contextual conditioning [33,30,132,135]. Research with KO mice has demonstrated that the effects of nicotine on hippocampus-dependent forms of learning require the β2 nAChR subunit.…”

Measurement of affective state during chronic nicotine treatment and withdrawal by affective taste reactivity in mice: The role of endocannabinoids

“…Osmotic pumps (Alzet, Durect Coporation, Cupertino, CA) were used to continuously infuse 0.9% NaCl vehicle or nicotine (Sigma-Aldrich, Tokyo, Japan) at a dose of 12 mg/kg/day of free base (32.4 mg/kg/day nicotine salt, pH corrected to 7.2 ± 0.2 using 1M NaOH) [35,36].…”

“…An intermediate nicotine dose (12 mg/kg/day) was employed based on previous studies in which termination of 6.3 -24 mg/kg/day nicotine produced an abstinence syndrome in terms of physical withdrawal, contextual fear responses and anxiety-like behaviors [35,36,67,68].Thus, taste reactivity may simply be unable to, or be insufficient to detect an affective mg/kg/day of nicotine [69], however, another study reported a dose of 40 mg/kg over 28 days was needed to produce changes in ICSS thresholds [70]. Furthermore, motivational impairment as measured by ICSS is precipitated at lower doses of a nicotinic antagonist than somatic signs of withdrawal [54,70].…”