CUE-DRIVEN NICOTINE MOTIVATED BEHAVIORS: INSIGHTS FROM A NOVEL ESCALATION MODEL

Nicotine addiction is the most prevalent addiction worldwide and a leading cause of preventable morbidity and mortality. Besides its reinforcing properties, nicotine also enhances responses to associated environmental stimuli, an effect that might contribute to the development of nicotine addiction and trigger relapse. Several lines of evidence indicate gender differences in smoking behavior. Here, we investigated nicotine-cue interactions in male and female rats using a newly developed escalation model of nicotine self-administration (SA), in which nicotine doses increased (30–240 µg/kg; ES group) versus a fixed-dose control (30 µg/kg; NOES group). Animals in the ES group escalated their intake and self-administered more nicotine than rats in the NOES group, with no sex differences. However, while both cue and nicotine are necessary to maintain nicotine SA in NOES rats, nicotine alone sustains nicotine SA in both sexes in ES rats. Males in both groups developed similar locomotor sensitization to nicotine as NOES females, while ES females decreased their locomotor activity over time. Moreover, although nicotine-seeking behavior extinguished rapidly, ES rats were more resistant to extinction than NOES in both sexes. Finally, though cue-lever contingency is critical to nicotine-induced reinstatement in all extinguished rats, no differences in drug-seeking was observed between groups. Together, these results show sex differences only in psychomotor sensitization to nicotine, and indicate that nicotine intake escalation alters the psychopharmacological mechanisms underlying nicotine-taking and -seeking behaviors, NOES rats seeking nicotine to enhance the reinforcing effects of the discrete cue, while ES rats sought nicotine primarily for its reinforcing effect.