Poor inhibitory control predicts sex-specific vulnerability to nicotine rewarding properties in mice

The risk of becoming addicted to tobacco varies greatly from individual to individual, raising the possibility of behavioural biomarkers capable of predicting sensitivity to nicotine reward, a crucial step in the development of nicotine addiction. Amongst all of nicotine's pharmacological properties, one of central importance is the enhancement of cognitive performances, which depend on the balance between attentional processes and inhibitory control. However, whether the cognitive enhancement effects of nicotine are predictive of sensitivity to its rewarding properties is still unknown.

Using male and female mice, we investigated whether the effects of nicotine on cognitive performances are predictive of sensitivity to the rewarding properties of nicotine and, if so, whether this relationship is sex dependent.

Naïve male and female mice were first assessed for their performances in both baseline conditions and following nicotine injection (0.15 and 0.30 mg/kg) in a cued-Fixed Consecutive Number task (FCNcue) measuring both optimal (attention) and premature (inhibitory control) responding. Next, all mice underwent nicotine-induced conditioned place preference (CPP) in order to evaluate inter-individual differences in response to nicotine reward (0.30 mg/kg).

Results showed that males and females benefited from the effect of nicotine as a cognitive enhancer in the FCNcue task. However, only those males displaying poor inhibitory control, namely high-impulsive animals, subsequently displayed sensitivity to nicotine reward. In females, sensitivity to nicotine reward was independent of FCNcue performances, in both basal and nicotine conditions.

Thus, our study suggests that poor inhibitory control and its modulation by nicotine may be a behavioural biomarker for sensitivity to nicotine reward and consequent vulnerability to nicotine addiction in males but not females.