Journal
NEUROPSYCHOPHARMACOLOGY
Volume 36, Issue 10, Pages 2111-2124Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2011.103
Keywords
motivation; self-administration; metabotropic glutamate receptor; microdialysis; dopamine
Categories
Funding
- National Institutes of Health [DA11946, MH080001]
- Tobacco-Related Disease Research Program of the State of California [19FT-0045]
- Swiss National Science Foundation [SNF-PBZHB-108501, SSMBS 1246]
- F Hofmann-La Roche Ltd (Basel, Switzerland)
- Intracellular Therapeutics Inc.
- Lundbeck Research USA Inc.
- Bristol-Myers Squibb Co.
- F Hoffman-La Roche Ind.
- Pfizer
- Abbott GmbH and Company
- AstraZeneca
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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-naive 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-naive 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-naive 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. Neuropsychopharmacology (2011) 36, 2111-2124; doi: 10.1038/npp.2011.103; published online 8 June 2011
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