Serotonin 2B receptors in mesoaccumbens dopamine pathway regulate cocaine responses

Doly, Stéphane; Quentin, Emily; Eddine, Raphaël; Tolu, Stefania; Fernández, Sebastián Pablo; Bertran González, Jesús; Valjent, Emmanuel; Belmer, Arnauld; Viñals Álvarez, Xavier, 1985-; Callebert, Jacques; Faure, Philippe; Meye, Frank Julius; Hervé, Denis; Robledo, Patricia, 1958-; Mameli, Manuel; Launay, Jean Marie; Maldonado, Rafael, 1961-; Maroteaux, Luc

Serotonin 2B receptors in mesoaccumbens dopamine pathway regulate cocaine responses

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dc.contributor.author Doly, Stéphaneca
dc.contributor.author Quentin, Emilyca
dc.contributor.author Eddine, Raphaëlca
dc.contributor.author Tolu, Stefaniaca
dc.contributor.author Fernández, Sebastián Pabloca
dc.contributor.author Bertran González, Jesúsca
dc.contributor.author Valjent, Emmanuelca
dc.contributor.author Belmer, Arnauldca
dc.contributor.author Viñals Álvarez, Xavier, 1985-ca
dc.contributor.author Callebert, Jacquesca
dc.contributor.author Faure, Philippeca
dc.contributor.author Meye, Frank Juliusca
dc.contributor.author Hervé, Denisca
dc.contributor.author Robledo, Patricia, 1958-ca
dc.contributor.author Mameli, Manuelca
dc.contributor.author Launay, Jean Marieca
dc.contributor.author Maldonado, Rafael, 1961-ca
dc.contributor.author Maroteaux, Lucca
dc.date.accessioned 2018-03-23T13:18:43Z
dc.date.available 2018-03-23T13:18:43Z
dc.date.issued 2017
dc.description.abstract Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT2B-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT2B receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting in vivo properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to ex vivo dopamine neurons were found in mice lacking 5-HT2B receptors. These data support the idea that the chronic 5-HT2B-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.
dc.description.sponsorship This work was supported by the Ministerio de Economía y Competitividad (#SAF2014-9648-P to R.M., MINECO/FEDER, UE); the Instituto de Salud Carlos III (RD06/0001/0001 to R.M.; PI14/00210 to P.R.), the FEDER funds; the Generalitat de Catalunya ICREA (Institució Catalana de Recerca i Estudis Avançats) Academia (2015) to R.M. The studies on Htr2b-/- mice were supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, and by grants from the Fondation pour la Recherche sur le Cerveau, the Fondation de France, the Fondation pour la Recherche Médicale "Equipe FRM DEQ2014039529", the French Ministry of Research (Agence Nationale pour la Recherche ANR-12-BSV1-0015-01 and the Investissements d'Avenir programme ANR-11-IDEX-0004-02). S.D. was supported by a Lefoulon-Lalande fellowship and E.Q. by a PhD fellowship from the Region Ile de France DIM Cerveau et Pensée. L.M.'s team is part of the École des Neurosciences de Paris Ile-de-France network and of the Bio-Psy Labex.
dc.format.mimetype application/pdf
dc.identifier.citation Doly S, Quentin E, Eddine R, Tolu S, Fernandez SP, Bertran-Gonzalez J et al. Serotonin 2B receptors in mesoaccumbens dopamine pathway regulate cocaine responses. J Neurosci. 2017 Oct 25;37(43):10372-88. DOI: 10.1523/JNEUROSCI.1354-17.2017
dc.identifier.doi http://dx.doi.org/10.1523/JNEUROSCI.1354-17.2017
dc.identifier.issn 1355-6215
dc.identifier.uri http://hdl.handle.net/10230/34259
dc.language.iso eng
dc.publisher Society for Neuroscienceca
dc.relation.ispartof Journal of Neuroscience. 2017 Oct 25;37(43):10372-88
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-9648-P
dc.rights © The Authors. Published by the Society for Neuroscience https://doi.org/10.1523/JNEUROSCI.1354-17.2017. The work is published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, as described at https://creativecommons.org/licenses/by/4.0/
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Cocaine self-administration
dc.subject.keyword Electrophysiological recordings
dc.subject.keyword Mesolimbic dopamine neurons
dc.subject.keyword Mouse knock-out
dc.subject.keyword Retrograde tracing
dc.subject.keyword Serotonin receptors
dc.title Serotonin 2B receptors in mesoaccumbens dopamine pathway regulate cocaine responsesca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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