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Prefrontal synaptic markers of cocaine addiction-like behavior in rats

Molecular Psychiatry volume 18, pages 729–737 (2013)Cite this article

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Abstract

Defining the drug-induced neuroadaptations specifically associated with the behavioral manifestation of addiction is a daunting task. To address this issue, we used a behavioral model that differentiates rats controlling their drug use (Non-Addict-like) from rats undergoing transition to addiction (Addict-like). Dysfunctions in prefrontal cortex (PFC) synaptic circuits are thought to be responsible for the loss of control over drug taking that characterizes addicted individuals. Here, we studied the synaptic alterations in prelimbic PFC (pPFC) circuits associated with transition to addiction. We discovered that some of the changes induced by cocaine self-administration (SA), such as the impairment of the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) was similarly abolished in Non-Addict- and Addict-like rats and thus unrelated to transition to addiction. In contrast, metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) was specifically suppressed in Addict-like rats, which also show a concomitant postsynaptic plasticity expressed as a change in the relative contribution of AMPAR and NMDAR to basal glutamate-mediated synaptic transmission. Addiction-associated synaptic alterations in the pPFC were not fully developed at early stages of cocaine SA, when addiction-like behaviors are still absent, suggesting that pathological behaviors appear once the pPFC is compromised. These data identify specific synaptic impairments in the pPFC associated with addiction and support the idea that alterations of synaptic plasticity are core markers of drug dependence.

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Acknowledgements

This work was supported by INSERM, Région Aquitaine, ANR grant (2005; P-VP and OM), EU-STREP-PheCOMP grant (FP6; P-VP), MILDT/INCa/INSERM grant (2008; VD-G and OM) and AXA Research Fund (FK). We thank A Le Roux and V Roullot-Lacarriére for their technical assistance with the western blot experiments.

Author contributions: FK and ML performed the electrophysiology experiments, conducted the data analyses and contributed to the design of the experiments. VD-G designed and supervised the behavioral experiments, and conducted the data analyses. J-MR designed and conducted the immunoblotting analyses. NB, EB, J-FF and PR conducted the behavioral experiments. P-VP and OJM supervised the entire project. FK, VD-G, P-VP and OJM wrote the manuscript.

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Author notes

  1. O J Manzoni

    Present address: 3Current address: INSERM U901, INMED, Université de la Méditerranée UMR S901 Aix-Marseille 2, Marseille 13009, France.,

  2. F Kasanetz, M Lafourcade and V Deroche-Gamonet: These authors contributed equally to this work.

  3. P-V Piazza and O J Manzoni: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, Bordeaux, France

    F Kasanetz, M Lafourcade, V Deroche-Gamonet, J-M Revest, N Berson, E Balado, J-F Fiancette, P Renault, P-V Piazza & O J Manzoni

  2. Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, Université de Bordeaux, Bordeaux, France

    F Kasanetz, M Lafourcade, V Deroche-Gamonet, J-M Revest, N Berson, E Balado, J-F Fiancette, P Renault, P-V Piazza & O J Manzoni

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Kasanetz, F., Lafourcade, M., Deroche-Gamonet, V. et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol Psychiatry 18, 729–737 (2013). https://doi.org/10.1038/mp.2012.59

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