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Cocaine increases dopaminergic connectivity in the nucleus accumbens

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Abstract

The development of addictive behavior is associated with functional and structural plasticity in the mesocorticolimbic pathway. Increased connectivity upon cocaine administration has been inferred from increases in dendritic spine density, but without observations of presynaptic elements. Recently, we established a method that enables analyses of both dendritic spines and glutamatergic boutons and presented evidence that cocaine induces changes in striatal connectivity. As the pharmacological and behavioral effects of cocaine directly implicate dopaminergic neurons and their afferents, a remaining question is whether dopaminergic striatal innervations also undergo structural plasticity. To address this issue, we generated transgenic mice in which the fluorophore tdTomato is expressed under the promoter of the dopamine transporter gene. In these mice, specific labeling of dopaminergic boutons was observed in the striatum. Of note, the accordance of our results for control mice with previous electron microscopy studies confirms that our method can be used to decipher the spatial organization of boutons in relation to dendritic elements. Following repeated cocaine administration that led to behavioral locomotor sensitization, an increased density of dopaminergic boutons was observed 1 day later in the nucleus accumbens shell specifically, and not in other striatal regions. Combined labeling of dopaminergic boutons and striatal dendrites showed that cocaine significantly increased the percentage of dendritic spines associated with a dopaminergic bouton. Our results show that chronic cocaine administration induces structural plasticity of dopaminergic boutons that could participate in dopamine-dependent neuronal adaptations in the striatum.

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Acknowledgements

We thank Francois Tronche for providing the DAT-Cre mouse line, and the Cellular Imaging facility of the IBPS (Institut de Biologie Paris-Seine) for expert assistance on microscopy and metrological control of the setup. This work was supported by Centre National pour la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), University Pierre and Marie Curie (UPMC), Agence Nationale de la Recherche (ANR), Fondation pour la Recherche Médicale (FRM) and the Labex Bio-Psy cluster of excellence. M.D.S. was a recipient of a fellowship from French Ministry of Research and Labex Bio-Psy. E.N.C. was supported by the Ecole de Neuroscience de Paris (ENP) and FRM.

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  1. Emma N. Cahill

    Present address: Department of Psychology, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

  2. Gregory Dal Bo

    Present address: Département de Toxicologie et risque chimiques, IRBA, Brétigny sur Orge, France

Authors and Affiliations

  1. Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine, Institut de Biologie Paris Seine (NPS, IBPS), 75005, Paris, France

    Marc Dos Santos, Emma N. Cahill, Peter Vanhoutte, Jocelyne Caboche, Bruno Giros & Nicolas Heck

  2. Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, QC, Canada

    Gregory Dal Bo & Bruno Giros

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  1. Marc Dos Santos
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Correspondence to Nicolas Heck.

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Dos Santos, M., Cahill, E.N., Bo, G.D. et al. Cocaine increases dopaminergic connectivity in the nucleus accumbens. Brain Struct Funct 223, 913–923 (2018). https://doi.org/10.1007/s00429-017-1532-x

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