Varenicline, the clinically effective smoking cessation agent, restores probabilistic response reversal performance during withdrawal from nicotine

Abstract

There is recognition that cognitive problems can contribute to renewed drug taking in former addicts. Our previous work has indicated that current smokers show reduced performance on a probabilistic reversal learning (PRL) task, relative to former smokers. To further explore PRL performance and its relevance to smoking, in addition to the role of nicotine, we developed a model of nicotine withdrawal-induced deficits in rodents. A second goal was to test varenicline, an α4β2 partial agonist, for its ability to restore any cognitive impairment. Acute effects of nicotine and varenicline on PRL performance in non-dependent animals were minimal and confined to speed of responding. When rats were made dependent on nicotine via osmotic minipumps implanted for 7 days (3.16 mg/kg/day), repeated tests at specified withdrawal time points revealed PRL disruption peaking at 12 and 24 hours following surgical removal of minipumps. Withdrawal was characterized by significant deficits in the number of reversals (P < 0.05), speed of responding (P < 0.01) and increases in omissions (P < 0.05). Nicotine (0.2 mg/kg SC) or varenicline (0.3 and 1.0 mg/kg SC) administered 10-minute prior to PRL test sessions during withdrawal, relieved the performance deficits. At 24-hour withdrawal, nicotine and varenicline (1 mg/kg) prevented decrements in reversals, in addition to ameliorating slower speed of responding. The high dose of varenicline only reduced omissions. These results confirm the role of nicotine in withdrawal-induced disruption of PRL performance and suggest that the model may be useful for investigating efficacy of potential new treatments for smoking cessation.

Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats

“…Daily treatment with CBD prevented the somatic signs of withdrawal at all doses tested. The effect size observed with the highest dose of CBD (Cohen's d = 1.6, 30 mg/kg/day) is similar to effect size observed after varenicline and bupropion (Cohen's d ~ 1.9 and ~ 1.5, respectively) during behavioral measurements of withdrawal in rodents (Cryan, Bruijnzeel et al 2003, Malin, Lake et al 2006, Damaj, Grabus et al 2010, Jackson, Silk et al 2017, Bagdas, Alkhlaif et al 2018. This comparison raises the possibility that CBD may produce similar therapeutic efficacy with fewer side effects, as CBD is generally well tolerated with low risk of serious adverse events or dependence (Viudez-Martinez, Garcia-Gutierrez et al 2019, Larsen andShahinas 2020).…”

Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers

“…Probabilistic reversal learning is a promising measure of cognitive flexibility and perseveration in addiction, with impaired performance in alcohol, cocaine, and amphetamine dependence . Rodent studies indicate that chronic administration of nicotine impairs cognitive flexibility during reversal learning and that acute delivery of nicotine or varenicline tartrate alleviates withdrawal-induced reversal learning deficits in nicotine-dependent animals . Despite relevance to nicotine withdrawal and subsequent relapse, to our knowledge, the interacting effects of nicotine dependence and acute stimulation of nAChRs on reward sensitivity and cognitive flexibility during PRL have not been characterized in humans.…”

Impact of Substance Use Disorder Pharmacotherapy on Executive Function: A Narrative Review

“…Nicotine administration at high (18 mg/Kg/day × 4 weeks) but not low dose (6.3 mg/Kg/day × 4 weeks) also impaired cognitive flexibility (increased perseverative responding to previously non-reinforced stimuli in a reversal learning task) in mice (56). Conversely, improvements in cognitive flexibility (attentional set-shifting task) and reversal of nicotine withdrawal-induced impairment in cognitive flexibility (reversal learning task) have both been reported in rats (57, 58). While in another human study, cognitive flexibility (attentional switching on the flexibility of attention test) was not changed by nicotine (59).…”

“…However, varenicline reduced ketamine-induced impairments in reversal learning (accuracy and perseverative responding) and improved working memory (accuracy at long delays on a delay match to sample task) in rhesus and pigtail monkeys (88). In studies related more specifically to smoking, varenicline reversed nicotine withdrawal-induced deficits in the number of reversals on a probabilistic reversal learning task administered to rats (58). While in a human study comparing 24 abstinent smokers with 20 non-smokers, impairments on a reversal learning task (increased response shifting with decisions less sensitive to available evidence) found in abstinent smokers were attenuated by varenicline.…”