Chronic but not acute N-acetylcysteine promotes extinction of nicotine-cue conditioned responding

A growing body of evidence indicates that restoring basal concentrations of extracellular glutamate and thereby increasing tonic activation of the mGluR2/3 receptors could be an important target for treatment of nicotine dependence. In fact, administration of N-acetylcysteine (N-AC), a cysteine prodrug, by restoring extracellular glutamate concentrations prevents relapse to cocaine- and heroin-seeking behavior in rats following drug self-administration. Thus, using a reliable procedure of extinction-reinstatement following nicotine self-administration inducing robust and lasting drug-seeking behavior (Di Clemente et al., 2012; Cervo et al., 2013) we characterized the efficacy of N-AC in modulating nicotine-seeking behavior in Wistar male rat. Acute pre-treatment with N-AC 100 mg/kg i.p., but not 30 and 60 mg/kg, induced a short-term attenuation of conditioned nicotine- but not saccharin-seeking behavior without influencing rats’ locomotor activity. This effect was completely prevented by 1 mg/kg LY341495, a selective group II metabotropic glutamate receptors (mGluR2/3) antagonist. Chronic treatment with N-AC 100 mg/kg i.p., but not 60 mg/kg, during 14th days exposure to nicotine-associated cues reduced drug-seeking without any tolerance. Moreover, chronic N-AC induced a long-term anti-relapse activity that was still present 14 days after the end of the treatment. In conclusion, N-AC might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking and that chronic treatment with N-AC may promote extinction of nicotine-cue conditioned responding.