title: mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine.
abstract: 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 (0.03 mg/kg/65 µl/2-second/infusion) or oral saccharin (100 µl of 50 mg/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 30 mg/kg i.p., reduced cue-induced nicotine-seeking. N-AC 100 mg/kg did not modify cue-induced saccharin-seeking behavior or influenced locomotor activity. Blocking mGluR2/3 with the selective antagonist LY341495, 1 mg/kg i.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.
authors: Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Italy.
authors: Federico
authors: F
authors: Moro
authors: Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Italy.
authors: Alessandro
authors: A
authors: Orrù
authors: Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Italy.
authors: Claudio Marcello
authors: CM
authors: Marzo
authors: Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Italy.
authors: Angelo
authors: A
authors: Di Clemente
authors: Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Italy.
authors: Luigi
authors: L
authors: Cervo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012646:Self Administration; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D018722:Nicotinic Agonists; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D009538:Nicotine; D000111:Acetylcysteine
keywords: Drug-associated cues; N-acetylcysteine; nicotine-seeking behavior