Chronic n-acetylcysteine treatment promotes extinction of conditioned cue-induced nicotine-seeking behavior in the rat

Tobacco smoking is a chronic relapsing disorder and resumption is recurrent after abstinence. Although some pharmacological and psychosocial support can help smokers to quit, the high relapse rates indicate a need for more efficacious treatments. A large body of evidence indicate 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, which normalize extracellular glutamate (Glu), restoring tone on pre-synaptic inhibitory mGluR2/3 auto-receptors in the nucleus accumbens, thus blunting the increased Glu release associated with drug cues-induced reinstatement of drug-seeking. Although nicotine-cues reinstate drug-seeking and increase extracellular Glu in the nucleus accumbens, it is still unclear whether N-AC would inhibit cue-induced reinstatement in abstinent rats after nicotine self-administration. Moreover, it is unknown whether restoring Glu homeostasis by chronic N-AC treatment would enhance the outcome of cue-exposure therapy for smoking cessation. To gain such information, we used an animal model of cue-induced robust and lasting nicotine-seeking in abstinent rats. We found that a single dose of N-AC (100 mg/kg) increased Glu extracellular release in the nucleus accumbens and induced a short-term reduction of cues-induced nicotine-seeking without altering cues-induced saccharin-seeking and rats’ locomotor activity. Pre-treatment with LY341495 (1 mg/kg), a selective mGluR2/3 antagonist, completely prevented N-AC from reducing cues-induced nicotine-seeking behavior. When N-AC (100 mg/kg) was given chronically before daily lever-presses extinction, during abstinence or in combination with nicotine-associated cues induced reinstatement, it was found that only in the latter condition N-AC not only showed efficacy when biologically available during testing, but also produced a long-lasting anti-relapse activity that was still present 2 weeks later. These results suggest that N-AC might offer a therapeutic opportunity in promoting extinction of nicotine-cue conditioned responding.