title: Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms.
abstract: L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.
authors.affiliation: Dipartimento di Filosofia, Scienze Sociali, Umane e della Formazione, Università degli Studi di Perugia, 06123 Perugia, Italy; Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
authors.forename: Desiree
authors.initials: D
authors.lastname: Mineo
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Vannelli
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Cacace
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.affiliation: CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: di Maio
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mellone
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stanic
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Fisiologia, Università degli Studi di Cagliari, 09124 Cagliari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tronci
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Fisiologia, Università degli Studi di Cagliari, 09124 Cagliari, Italy.
authors.forename: Camino
authors.initials: C
authors.lastname: Fidalgo
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Fisiologia, Università degli Studi di Cagliari, 09124 Cagliari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Stancampiano
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Fisiologia, Università degli Studi di Cagliari, 09124 Cagliari, Italy.
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy; Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy; Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli (SUN), 81100 Caserta, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy. Electronic address: b.picconi@hsantalucia.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D007980:Levodopa; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications*; D010879:Piperazines / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage*; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D010879:Piperazines; D017366:Serotonin Receptor Agonists; D007980:Levodopa; C063828:eltoprazine; D016627:Oxidopamine; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: Bidirectional synaptic plasticity; Levodopa treatment; Parkinson's disease animal models; Serotonergic transmission