Acute nicotine administration reduces the efficacy of punishment in curbing remifentanil consumption in a seeking-taking chain schedule of reinforcement

Rationale: Nicotine dependence is highly comorbid with opioid use disorders (OUDs). The use of nicotine-containing products increases the propensity to misuse prescription opioids and addressing both nicotine and opioid use simultaneously is more efficacious for treatment of OUDs than treating opioid use alone. Objectives: Given this extreme comorbidity, further elucidation of the effects of nicotine as a factor in promoting vulnerability to development of OUDs is needed. Here, we sought to further explore the effects of nicotine administration on operant self-administration of remifentanil (RMF), a fast-acting synthetic µ-opioid receptor agonist, using a heterogenous seeking–taking chain schedule of reinforcement in unpunished and punished conditions. Methods: Male and female rats received nicotine (0.4 mg/kg) or saline prior to operant self-administration sessions. These sessions consisted of pressing a ‘seeking’ lever to gain access to a ‘taking’ lever that could be pressed for delivery of 3.2 µg/kg RMF. After acquisition, continued drug seeking/taking was punished through contingent delivery of foot-shock. Results: Nicotine, relative to saline, increased RMF consumption. Furthermore, nicotine treatment resulted in significantly higher seeking responses and cycles completed, and this effect became more pronounced during punished sessions as nicotine-treated rats suppressed RMF seeking significantly less than controls. Nicotine treatment functionally reduced the efficacy of foot-shock punishment as a deterrent of opioid-seeking. Conclusions: Nicotine administration enhanced both appetitive and consummatory responding for RMF and engendered a punishment-insensitive phenotype for RMF that was less impacted by contingent administration of foot-shock punishment. These findings provide further support for the hypothesis that nicotine augments vulnerability for addiction-like behaviors for opioids.