Effects of single and repeated N-acetylcysteine on cue-induced nicotine-seeking behavior in rats

The inability of smokers to control relapse to drug-seeking behavior is a key feature of nicotine addiction. A large body of evidence indicates that the cysteine pro-drug N-acetylcysteine (N-AC) may have beneficial therapeutic effects in the treatment of drug addiction. In humans, pilot studies have shown that N-AC decreases drug cues-induced craving for cocaine, number of cigarettes smoked, and marijuana use and craving. Pre-clinically N-AC reduced conditioned cues-induced cocaine- and heroin-seeking by restoring cystine-glutamate exchange system Xc- and the glial glutamate transporter GLT1, normalizing extracellular glutamate in the nucleus accumbens (Nacc), thus blunting the activation of glutamatergic neurons associated with drug cues-induced reinstatement. Although nicotine-associated cues reinstate drug-seeking, it is still not clear whether N-AC can inhibit cue-induced reinstatement in abstinent rats after nicotine self-administration. It is also not clear whether restoring Glu homeostasis by chronic N-AC treatment can enhance the outcome of cue-exposure therapy (CET) for smoking cessation. To gain this information we used rats trained to associate discriminative stimuli (SDs) with intravenous nicotine or oral saccharin self-administration vs. no-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Re-exposure to nicotine or saccharin SD+/CS+, but not no-reward SD-/CS-, revived responding at the previously reinforced lever. A single dose of N-AC (100 mg/kg) induced a short-term reduction of cues-induced nicotine-seeking that was completely prevented by pre-treatment with the selective mGluR2/3 antagonist LY341495 (1 mg/kg i.p.). Chronic treatment with N-AC (100 mg/kg) during 14 days’ of CET, but not forced abstinence, induced lasting anti-relapse activity that was still present 50 days after the end of treatment. To provide a mechanism for behavioral results, separate groups of rats that received either N-AC or vehicle treatments in combination with CET were killed for proteins analysis. Interestingly, western blot analysis of punches containing Nacc-core and Nacc-shell revealed that chronic N-AC reverted changes in the levels of the catholic subunit of system Xc- and GLT1 found in vehicle-treated rats. These results, provided they can be extrapolated to smokers, suggest the potential therapeutic use of N-AC for acute cue-controlled nicotine-seeking and to promote extinction of nicotine-cue conditioned responding.