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Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice

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Abstract

Rationale

Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known.

Objectives

In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2 subunit-containing nAChR gene (β2+/− or β2−/−) performing an operant cognitive flexibility task.

Results

Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2−/− mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/− mice.

Conclusions

Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies.

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Acknowledgments

The studies were supported by Brain and Behavior Research Foundation (V.P.) and partly by grants from the National Institute of Health (NIH) DA 017949 and CA 143187 (T.J.G.). D.G. was supported by MARC Undergraduate Student Training in Academic Research (NIH 5T34 GM 087239). We thank David Braak for the assistance with the genotyping.

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Cole, R.D., Poole, R.L., Guzman, D.M. et al. Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice. Psychopharmacology 232, 1207–1217 (2015). https://doi.org/10.1007/s00213-014-3754-4

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