N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine-seeking in rats

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Rationale Chronic nicotine administration decreases the functioning of the cystine-glutamate antiporter system xc_ which is hypothesized to promote nicotine-taking and -seeking behaviors. N-acetylcysteine (NAC), a cystine pro-drug, increases the activity of the cystine-glutamate antiporter system xc_. Thus, NAC could potentially reverse nicotine-induced alterations in glutamatergic transmission and decrease nicotine taking and seeking. Objectives and Methods To test this hypothesis in the present study, the effects of acute NAC treatment (30, 60, 90 mg/kg i.p.) on nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration were assessed in rats. In addition, the effects of acute NAC treatment on cue-induced reinstatement of nicotine- and food-seeking behaviors were investigated. Finally, the effects of repeated daily NAC administration (60 mg/kg, i.p., 14 days) on nicotine and food self-administration were assessed. Results Acute NAC administration decreased nicotine self-administration but not food responding under a fixed-ratio schedule of reinforcement. In addition, acute NAC administration showed a non-significant trend in attenuating nicotine self-administration under a progressive-ratio schedule that was similar to the dose-response function under the fixed-ratio schedule. Furthermore, repeated NAC administration decreased nicotine self-administration from day 6 to 14 compared with vehicle treatment, with no indication of tolerance development. By contrast, repeated NAC administration decreased food responding from day 6 to 8 compared with vehicle treatment, and showed rapid development of tolerance. Finally, NAC administration attenuated cue-induced reinstatement of nicotine and food seeking. Conclusions Altogether, these findings suggest that NAC may be useful in promoting smoking cessation in humans.