Abstract
Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 3′-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse.
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This work was supported by National Institutes of Health grant R01 DA023926 to NC. We thank Ms Kim Edwards and Mrs Jessica Benedict for technical assistance and Mr Michael Arends for editorial assistance.
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AM has received contract research support from Intracellular Therapeutics, Lundbeck Research USA, Bristol–Myers Squibb, F Hoffman-La Roche, Pfizer, and Astra-Zeneca and honorarium/consulting fees from Abbott GmbH and Company, AstraZeneca, and Pfizer during the past 3 years. AM and SS have a patent application on metabotropic glutamate receptors and drug dependence. PJC receives research support, including salary support, from Seaside Therapeutics and Johnson and Johnson and has received consulting fees or speaking honoraria from Eli Lilly and Company, Invitrogen, Roche Pharmaceutical, Cephalon, AstraZeneca, Bristol–Myers Squibb, Addex, Forest Research Institute, LEK Consulting, Merck and Company, Epix Pharmaceuticals, AMRI, Evotec, Millipore, Genentech, IMS Health, Sepracor, Seaside Therapeutics, Lundbeck Research, Otsuka Pharmaceuticals, Prestwich Pharmaceuticals, Primary Insight, The Frankel Group, Metastatix, GlaxoSmithKline, Adolor, Abbott Laboratories, Merck Serono, Johnson and Johnson, Solvay, and PureTech during the past 3 years. PJC is an inventor on multiple patents and pending patent applications on specific allosteric modulators of GPCRs, none of which is included in this study. NC has received research support from Brain Cells and honorarium/consulting fees from Vertex Pharmaceuticals during the past 3 years. The remaining authors declare no conflict of interest.
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Jin, X., Semenova, S., Yang, L. et al. The mGluR2 Positive Allosteric Modulator BINA Decreases Cocaine Self-Administration and Cue-Induced Cocaine-Seeking and Counteracts Cocaine-Induced Enhancement of Brain Reward Function in Rats. Neuropsychopharmacol 35, 2021–2036 (2010). https://doi.org/10.1038/npp.2010.82
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