title: Central serotonin(2B) receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow.
abstract: The central serotonin2B receptor (5-HT2BR) is currently considered as an interesting pharmacological target for improved treatment of drug addiction. In the present study, we assessed the effect of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on cocaine-induced hyperlocomotion and dopamine (DA) outflow in the nucleus accumbens (NAc) and the dorsal striatum of freely moving rats. The peripheral administration of RS 127445 (0.16 mg/kg, i.p.) or LY 266097 (0.63 mg/kg, i.p.) significantly reduced basal DA outflow in the NAc shell, but had no effect on cocaine (10 mg/kg, i.p.)-induced DA outflow in this brain region. Also, RS 127445 failed to modify both basal and cocaine-induced DA outflow in the NAc core and the dorsal striatum. Conversely, both 5-HT2BR antagonists reduced cocaine-induced hyperlocomotion. Furthermore, RS 127445 as well as the DA-R antagonist haloperidol (0.1 mg/kg, i.p.) reduced significantly the late-onset hyperlocomotion induced by the DA-R agonist quinpirole (0.5 mg/kg, s.c.). Altogether, these results demonstrate that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical DA outflow. This interaction takes place downstream to DA neurons and could involve an action at the level of dorsostriatal and/or NAc DA transmission, in keeping with the importance of these brain regions in the behavioural responses of cocaine. Overall, this study affords additional knowledge into the regulatory control exerted by the 5-HT2BR on ascending DA pathways, and provides additional support to the proposed role of 5-HT2BRs as a new pharmacological target in drug addiction.
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: celine.devroye@inserm.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Devroye
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: adeline.cathala@inserm.fr.
authors.forename: Adeline
authors.initials: A
authors.lastname: Cathala
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France. Electronic address: bbr.dimarco@gmail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Marco
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Department of Drug Sciences, University of Catania, Catania, 95125, Italy. Electronic address: filippo.caraci@inserm.fr.
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, 95125, Italy. Electronic address: fdrago@tin.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: pier-vincenzo.piazza@inserm.fr.
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Piazza
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: umberto.spampinato@inserm.fr.
authors.forename: Umberto
authors.initials: U
authors.lastname: Spampinato
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D011743:Pyrimidines; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; D019257:Quinpirole; D003042:Cocaine; D006220:Haloperidol; D004298:Dopamine
keywords: 5-HT(2B) receptor; Cocaine; Dopamine; Dorsal striatum; Nucleus accumbens; Rat