Impact of Withdrawal from Chronic Nicotine on Strategy Set-shifting in C57BLJ/6J Mice

Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacco use produces various somatic and affective signs of withdrawal during the firSt few days of abstinence, withdrawal-related cognitive deficits are considered to be the moSt critical symptoms that predict relapse. The present study was designed to examine the effects of precipitated nicotine withdrawal on cognitive control processes. We employed a mouse operant cognitive flexibility task that required the animals to shift attention from a visual cue to a spatial cue. Male C57BL/6J were implanted with subcutaneous osmotic minipumps to deliver either saline or nicotine (18mg/kg/day; base) for 4 weeks. Precipitated withdrawal was induced via a subcutaneous injection of mecamylamine, a non-specific nicotinic receptor antagonist (3 mg/kg), 20minutes before testing during the fourth week. Mice undergoing precipitated nicotine withdrawal required higher number of trials to attain criterion as compared to their respective controls. Error analysis indicated that impaired performance following nicotine withdrawal was mostly related to the animals' inability to maintain a new learning strategy rather than increased perseveration to the previously acquired strategy. Interestingly, mecamylamine treatment per se also disrupted this fonn of cognitive flexibility and these impainnents were associated with higher perseverative errors. These findings suggest that the ability to sustain cognitive control is disrupted during nicotine abstinence, which may lead to relapse.'