Effects of Chronic Low- and High-dose Nicotine on Cognitive Flexibility in C57BL/6J Mice

The addictive nature of nicotine remains a global health problem. Despite the availability of treatments for smoking cessation, relapse to smoking after quit attempts still remains very high. Here, we evaluated the effects of chronic nicotine in male C57BL/6J mice in an operant cognitive flexibility task that required the animals to progress sequentially through multiple phases including visual discrimination, strategy shifting and response reversal. As frontostriatal circuits involving discrete regions of dorsal striatum contribute directly to decision-making processes, and BDNF modulates synaptic plasticity and learning, we also assessed the effects of nicotine on striatal BDNF expression. Osmotic minipumps containing either of the two doses of nicotine (low: 6.3 mg/kg/day; high: 18 mg/kg/day) or saline (control) were implanted for chronic delivery that lasted 4 weeks. Nicotine-treated mice exhibited greater response accuracy during visual discrimination. Neither dose of nicotine affected learning of new egocentric response strategy during set-shifting. However, higher but not lower dose of nicotine impaired reversal learning by increasing perseverative responding to the previously non-reinforced stimulus. Furthermore, this effect was associated with reduced BDNF levels in the dorsal striatum. Collectively, these findings suggest that higher relapse rates often observed in high nicotine-dependent smokers may be attributed to impairments in inhibitory control processes. Moreover, striatal BDNF may play a critical role in nicotine-induced alterations in cognitive flexibility.