title: Serotonin2C receptor stimulation inhibits cocaine-induced Fos  expression and DARPP-32 phosphorylation in the rat striatum  independently of dopamine outflow.
abstract: The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.
authors.affiliation: Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux F-33000, France. celine.devroye@inserm.fr
authors.forename: Céline
authors.initials: C
authors.lastname: Devroye
authors.forename: Adeline
authors.initials: A
authors.lastname: Cathala
authors.forename: Marlène
authors.initials: M
authors.lastname: Maitre
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Piazza
authors.forename: Djoher Nora
authors.initials: DN
authors.lastname: Abrous
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Revest
authors.forename: Umberto
authors.initials: U
authors.lastname: Spampinato
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D005021:Ethylamines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005021:Ethylamines; D007211:Indoles; D016761:Oncogene Proteins v-fos; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D017366:Serotonin Receptor Agonists; D003042:Cocaine; D004298:Dopamine