Relapse to cotinine seeking in rats: differential effects of sex

Relapse is a defining feature of smoking and a significant challenge in cessation management. Elucidation of novel factors underlying relapse may inform future treatments. Cotinine, the major metabolite of nicotine, has been shown to support intravenous self-administration in rats, implicating it as one potential factor contributing to nicotine reinforcement. However, it remains unknown whether cotinine would induce relapse-like behaviors. The current study investigated relapse to cotinine seeking in two relapse models, the reinstatement of drug seeking and incubation of drug craving models. In the reinstatement model, rats were trained to self-administer cotinine, underwent extinction of cotinine-associated responses, and were tested for cue-, drug-, or stress-induced reinstatement. Conditioned cues associated with cotinine self-administration, cotinine (1-2 mg/kg), or the pharmacological stressor yohimbine (1.25-2.5 mg/kg) induced reinstatement of cotinine seeking. Female rats displayed more pronounced cue-induced, but not drug- or stress-induced reinstatement than male rats. In the incubation of the craving model, rats were trained to self-administer cotinine and underwent forced withdrawal in home cages. Rats were tested for cue-induced cotinine-seeking on both withdrawal day 1 and withdrawal day 18. Rats exhibited greater cue-induced cotinine-seeking on withdrawal day 18 compared to withdrawal day 1, with no difference between male and female rats. These findings indicate that cotinine induces sex-specific relapse to drug seeking in rats, suggesting that cotinine may contribute to relapse.