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

Ana M. Ramirez-Niño, University of California - San Diego
Manoranjan S. D’Souza, Ohio Northern University
Svetlana G. Semenova, University of California - San Diego
Athina M. Markou, University of California - San Diego


Chronic nicotine administration is hypothesized to disrupt corticolimbic glutamatergic neurotransmission and lead to a hypoglutamatergic state. N-acetylcysteine (NAC) increases extracellular glutamate levels by acting on the cystine-glutamate antiporter xc- which exchanges intracellular glutamate for extracellular cystine. Thus, NAC may reverse dysfunctions in glutamate transmission resulting from chronic nicotine exposure. Previously, NAC administration in smokers reduced the number of cigarettes smoked daily when alcohol consumption was taken into consideration. In the present study, we assessed the effects of acute NAC treatment on nicotine and food self-administration using a fixed ratio schedule of reinforcement in rats. Furthermore, the effects of acute NAC treatment on nicotine self-administration were also evaluated using a progressive ratio schedule. In addition, we tested the effects of NAC treatment on cue-induced reinstatement of nicotine-seeking behavior. Rats were treated with NAC (0, 30, 60, 90 mg/kg i.p.) in a within-subjects latin-square design, 2.5 hours prior to self-administration (nicotine or food) and cue-induced reinstatement sessions. Finally, we assessed the effects of repeated daily NAC (60 mg/kg) administration on nicotine and food self-administration. Acute NAC administration significantly decreased nicotine self-administration (n=20) in the fixed-ratio schedule, while having no effect on food responding (n=8). In the progressive ratio schedule, acute NAC administration did not significantly reduce break points for nicotine (n=14), although the dose-response function under the progressive ratio schedule was similar as that under the fixed-ratio schedule. Repeated NAC (n=14) significantly decreased nicotine self-administration compared to saline treatment (n=13), with no indication of tolerance development. By contrast, repeated NAC (n=8) decreased food responding compared to saline treatment (n=9), but responding gradually returned to baseline levels indicating tolerance. Furthermore, NAC attenuated cue-induced reinstatement (n=21) of nicotine-seeking behavior. The observed effects of NAC are possibly due to the enhancement of xc- activity and the restoration of reduced extracellular glutamate levels induced by chronic nicotine exposure; thus, eliminating the need for high nicotine intake and increased nicotine-seeking. In conclusion, the selective decrease in nicotine self-administration and the attenuation of cue-induced reinstatement by NAC indicate that NAC is a potential treatment for nicotine addiction and may potentially prevent relapse to tobacco smoking.