Effects of chronic low- and high-dose nicotine on cognitive flexibility in C57BL/6J mice

Abstract

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.

Nicotine Addiction and Psychiatric Disorders

“…The same study also reported that intradimensional set-shifting that entails switching within the same dimension was also facilitated by acute nicotine. However in a recent study conducted in our laboratory, chronic nicotine treatment for 4 weeks did not alter strategy set-shifting in an operant-based cognitive flexibility task in mice (Ortega, Tracy, Gould, & Parikh, 2013). Rather, it impaired reversal learning and these cognitive deficits were associated with increased perseverative responding to the previously rewarded stimulus indicating deficits in response inhibition.…”

Cognitive control deficits during mecamylamine-precipitated withdrawal in mice: Possible links to frontostriatal BDNF imbalance

“…Mice were trained in an operant cognitive flexibility task using standard mouse chambers (Med Associates) as described previously in our studies (Ortega et al, 2013, Cole et al, 2015; D’Amore et al, 2015). Briefly, animals were autoshaped on a FR-1 schedule of reinforcement to acquire lever press responses and subsequent reinforcement of reward (10μl of 0.066% saccharin solution).…”

Urinary Brain-Derived Neurotrophic Factor as a Biomarker of Executive Functioning

“…First,BDNF is known to play a critical role in nicotine-induced alterations incognitiveflexibility in mice [42]. Second, exogenous BDNF administration in mice facilitates set-shifting behavior by minimizing response perseveration [12], an effect that is dependent on activation of tropomyosin-related kinase B receptors on glutamatergic terminals.…”