N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking

Rationale

Chronic nicotine administration decreases the functioning of the cystine–glutamate antiporter system x_c? which is hypothesized to promote nicotine-taking and nicotine-seeking behaviors. N-acetylcysteine (NAC), a cystine pro-drug, increases the activity of the cystine–glutamate antiporter system x_c?. 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, and 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 nonsignificant 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, acute 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.