Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Abstract

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/ kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning.

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“…Mice withdrawn from nicotine spend less time on the open arms relative to saline controls, indicating increased anxiety [28,77].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.…”

Contextual conditioning in rats as an animal model for generalized anxiety disorder

“…Other antidepressants, such as bupropion XL (norepinephrine and dopamine reuptake inhibitor, as well as nicotinic antagonist), mirtazapine (noradrenergic and specific serotonergic antidepressant), and trazodone (serotonin-2/1C receptor antagonist), are effective in the treatment of GAD (Bystritsky, Kerwin, Feusner, & Vapnik, 2008;Gambi, De Berardis, Campanella, Carano, Sepede, Salini et al, 2005;Rickels, Downing, Schweizer, & Hassman, 1993). Accordingly, bupropion has anxiolytic effects in the CC model (Portugal & Gould, 2007). Dubovsky, 1990;Milanov, 2007 (-) Propranolol (40 mg Benzodiazepines are very valuable anxiolytics and have long been used to treat anxiety.…”

Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice

“…Although animal models have been used to examine the somatic and affective symptoms of nicotine withdrawal, less research has focused on the effects of nicotine withdrawal on learning and memory. One behavioral paradigm that has been used to examine the effects of nicotine on learning and memory is contextual fear conditioning [see 31 for review], and studies have consistently shown that acute nicotine enhances contextual conditioning, chronic nicotine does not alter contextual conditioning and nicotine withdrawal disrupts contextual conditioning [16,13,15,32,64,65].…”