Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms.
Neurobiology of Disease. 2016-02-01; 86: 140-153
DOI: 10.1016/j.nbd.2015.11.022
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Ghiglieri V(1), Mineo D(2), Vannelli A(2), Cacace F(2), Mancini M(2), Pendolino V(2), Napolitano F(3), di Maio A(4), Mellone M(5), Stanic J(5), Tronci E(6), Fidalgo C(6), Stancampiano R(6), Carta M(6), Calabresi P(7), Gardoni F(5), Usiello A(8), Picconi B(9).
Author information:
(1)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.
(2)Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma,
Italy.
(3)CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy; Dipartimento di Medicina
Molecolare e Biotecnologie Mediche, Università di Napoli « Federico II », 80131
Napoli, Italy.
(4)CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy.
(5)Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università
degli Studi di Milano, 20133 Milan, Italy.
(6)Dipartimento di Scienze Biomediche, Sezione di Fisiologia, Università degli
Studi di Cagliari, 09124 Cagliari, Italy.
(7)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.
(8)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.
(9)Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma,
Italy. Electronic address: .
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2015.11.022
PMID: 26639853 [Indexed for MEDLINE]