title: The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine-associated context in rats.
abstract: The metabotropic glutamate 2/3 (mGlu2/3) receptor agonist LY379268 ([-]-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate) attenuates both nicotine self-administration and cue-induced nicotine seeking in rats. In this study, the effects of LY379268 (1 mg/kg) or saline pretreatment on nicotine-induced increases in nucleus accumbens (NAcc) shell dopamine were evaluated using in vivo microdialysis under different experimental conditions: (i) nicotine (0.4 mg/kg, base) was experimenter-administered subcutaneously to nicotine-naïve rats; (ii) nicotine was experimenter-administered either subcutaneously (0.4 mg/kg) or by a single experimenter-administered infusion (0.06 mg/kg, base) in rats with a history of nicotine self-administration (nicotine experienced) in the absence of a nicotine-associated context (ie, context and cues associated with nicotine self-administration); (iii) nicotine (0.06 mg/kg) was self-administered or experimenter-administered in nicotine-experienced rats in the presence of a nicotine-associated context. In saline-pretreated nicotine-naïve and nicotine-experienced rats, nicotine increased NAcc shell dopamine regardless of the context used for testing. Interestingly, LY379268 pretreatment blocked nicotine-induced increases in NAcc shell dopamine in nicotine-experienced rats only when tested in the presence of a nicotine-associated context. LY379268 did not block nicotine-induced increases in NAcc shell dopamine in nicotine-naïve or -experienced rats tested in the absence of a nicotine-associated context. These intriguing findings suggest that activation of mGlu2/3 receptors negatively modulates the combined effects of nicotine and nicotine-associated contexts/cues on NAcc dopamine. Thus, these data highlight a critical role for mGlu2/3 receptors in context/cue-induced drug-seeking behavior and suggest a neurochemical mechanism by which mGlu2/3 receptor agonists may promote smoking cessation by preventing relapse induced by the combination of nicotine and nicotine-associated contexts and cues.
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Manoranjan S
authors.initials: MS
authors.lastname: D'Souza
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Liechti
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ramirez-Niño
authors.forename: Ronald
authors.initials: R
authors.lastname: Kuczenski
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018492:Dopamine Antagonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D009538:Nicotine; D004298:Dopamine