title: Opposite control of mesocortical and mesoaccumbal dopamine pathways by serotonin2Breceptor blockade: Involvement of medial prefrontal cortex serotonin1Areceptors.
abstract: Recent studies have shown that serotonin2Breceptor (5-HT2BR) antagonists exert opposite facilitatory and inhibitory effects on dopamine (DA) release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc), respectively, thereby leading to the proposal that these compounds could provide an interesting pharmacological tool for treating schizophrenia. Although the mechanisms underlying these effects remain unknown, several data in the literature suggest that 5-HT1ARs located into the mPFC could participate in this interaction. The present study, using in vivo microdialysis and electrophysiological recordings in rats, assessed this hypothesis by means of two selective 5-HT1AR (WAY 100635) and 5-HT2BR (RS 127445) antagonists. WAY 100635, administered either subcutaneously (0.16 mg/kg, s.c) or locally into the mPFC (0.1 μM), blocked the changes of mPFC and NAc DA release induced by the intraperitoneal administration of RS 127445 (0.16 mg/kg, i.p.). The administration of RS 127445 (0.16 mg/kg, i.p.) increased both dorsal raphe nucleus (DRN) 5-HT neuron firing rate and 5-HT outflow in the mPFC. Likewise, mPFC 5-HT outflow was increased following the intra-DRN injection of RS 127445 (0.032 μg/0.2 μl). Finally, intra-DRN injection of RS 127445 increased and decreased DA outflow in the mPFC and the NAc, respectively, these effects being reversed by the intra-mPFC perfusion of WAY 100635. These results demonstrate the existence of a functional interplay between mPFC 5-HT1ARs and DRN 5-HT2BRs in the control of the DA mesocorticolimbic system, and highlight the clinical interest of this interaction, as both receptors represent an important pharmacological target for the treatment of schizophrenia.
authors.affiliation: Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction and Traumatic Memories 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 U1208, Stem Cell and Brain Research Institute, 69500 Bron, France; Université Lyon 1, 69373 Lyon, France. Electronic address: nasser.haddjeri@inserm.fr.
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
authors.affiliation: Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction and Traumatic Memories 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 U1208, Stem Cell and Brain Research Institute, 69500 Bron, France; Université Lyon 1, 69373 Lyon, France. Electronic address: renaud.rovera@wanadoo.fr.
authors.forename: Renaud
authors.initials: R
authors.lastname: Rovera
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 U1215, Neurocentre Magendie, Physiopathology of Addiction and Traumatic Memories 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: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Rosselló 161, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain. Electronic address: francesc.artigas@iibb.csic.es.
authors.forename: Francesc
authors.initials: F
authors.lastname: Artigas
authors.affiliation: Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction and Traumatic Memories 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: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018492:Dopamine Antagonists; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D012702:Serotonin Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004298:Dopamine
keywords: 5-HT firing; 5-HT(1A) receptor; 5-HT(2B) receptor; Dopamine release; Dorsal raphe nucleus; Mesocorticolimbic dopamine system