mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine

Federico Moro, Alessandro Orrù, Claudio Marcello Marzo, Angelo Di Clemente, Luigi Cervo

Research output: Contribution to journalArticlepeer-review


Chronic self-administration of nicotine induces maladaptive changes in the cortico-accumbal glutamate (Glu) network. Consequently, re-exposure to nicotine-associated cues raises extracellular Glu in the nucleus accumbens reinstating drug-seeking. Restoring basal concentrations of extracellular Glu, thereby increasing tonic activation of the presynaptic group II metabotropic Glu receptors (mGluR2/3) with N-acetylcysteine (N-AC), might offer a valid therapeutic approach for maintaining smoking abstinence. Although N-AC modulates nicotine-seeking behavior by drug-associated stimuli in abstinent rats, it is still unclear whether it occurs through activation of mGluR2/3. Male Wistar rats were trained to associate discriminative stimuli (SDs) with the availability of intravenous nicotine (0.03mg/kg/65μl/2-second/infusion) or oral saccharin (100μl of 50mg/l) self-administration versus non-reward. Reinforced response was followed by a cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent lever press extinction, without reinforcers, SDs and CSs. Re-exposure to nicotine or saccharin SD+/CS+, but not non-reward SD-/CS-, revived responding on the previously reinforced lever. Acute N-AC, 100 but not 60 or 30mg/kgi.p., reduced cue-induced nicotine-seeking. N-AC 100mg/kg did not modify cue-induced saccharin-seeking behavior or influenced locomotor activity. Blocking mGluR2/3 with the selective antagonist LY341495, 1mg/kgi.p., completely prevented the antirelapse activity of N-AC. The finding that N-AC prevents cue-induced nicotine-seeking by stimulating mGluR2/3 might indicate a therapeutic opportunity for acute cue-controlled nicotine-seeking. Future studies could evaluate the persistent effects of chronic N-AC in promoting enduring suppression of nicotine-cue conditioned responding.

Original languageEnglish
Pages (from-to)28-40
JournalAddiction Biology
Publication statusPublished - 2018


  • Drug-associated cues
  • N-acetylcysteine
  • Nicotine-seeking behavior

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology
  • Psychiatry and Mental health


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