Increased drug seeking and vulnerability to relapse after escalation of nicotine intake by dose manipulation in male and female rats

Nicotine addiction is characterized by escalated drug use, craving and a high relapse rate after abstinence. Recently, we showed that, compared to rats with a fixed moderate dose of nicotine, rats with access to increasing high doses of nicotine for self-administration progressively escalated their nicotine intake. Whether these animals with escalating patterns of nicotine self-administration also develop other behavioral signs of addiction remains to be investigated. Here we report that after escalation of nicotine intake, animals have a greater difficulty of abstaining from seeking the drug, a greater responsiveness to nicotine-induced craving-like behavior, and an increased vulnerability to re-escalate nicotine intake post-extinction than rats with stable patterns of nicotine intake. No substantial sex differences in the development of these different addiction-related phenomena were observed. Finally, after escalation, nicotine intake also became primarily dependent on nicotine reinforcement and less so on the nicotine-paired cue. Overall, this study shows that most of the behavioral changes observed following escalation of nicotine self-administration are similar to those previously observed with other drugs of abuse.