Abstract
Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior.
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Acknowledgements
We would like to thank Dr Rick Bernardi for assisting with English editing. A special acknowledgement goes to Jean-Francois Fiancette, Prisca Renault, and Eric Balado for training NC. in Bordeaux. This work was supported by the Deutsche Forschungsgemeinschaft (DFG): Reinhart-Koselleck Award SP 383/5-1 and HA 6102/1-1.
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CC and MC were employed at Glaxo SmithKline and are currently employed at Aptuit. Over the past 3 years, RS has received compensations for research and consultant contracts from Abbott, AirLiquide, GSK, Lundbeck, Reckitt-Benckiser Pharmaceuticals, Roche, and Xenoport.
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NC established the ‘DSM-IV Based Rat Model of Cocaine Addiction’ at the Central Institute of Mental Health in Mannheim (Germany), performed LY379268 experiments, analyzed the data, coordinated the project, and wrote the manuscript; BH performed mice experiments and analyzed the data; SU and ACH performed in situ hybridization and analyzed the data; LE assisted NC in rat behavioral experiments; MC and CC provided mGluR3−/− mice; VDG trained NC in her laboratory for 5 weeks, gave trouble-shooting feedbacks during the establishment of the rat model in Mannheim, and contributed to the revision process; RS designed, supervised, supported the project and wrote the manuscript.
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Cannella, N., Halbout, B., Uhrig, S. et al. The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior. Neuropsychopharmacol 38, 2048–2056 (2013). https://doi.org/10.1038/npp.2013.106
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DOI: https://doi.org/10.1038/npp.2013.106
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