Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms

Paolo Calabresi, Veronica Ghiglieri, Desiree Mineo, Anna Vannelli, Fabrizio Cacace, Maria Mancini, Valentina Pendolino, Francesco Napolitano, Anna Di Maio, Manuela Mellone, Jennifer Stanic, Elisabetta Tronci, Camino Fidalgo, Roberto Stancampiano, Manolo Carta, Fabrizio Gardoni, Alessandro Usiello, Barbara Picconi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

28 Citazioni (Scopus)

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 involuntarymovements (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 striataldependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.
Lingua originaleEnglish
pagine (da-a)140-153
Numero di pagine14
RivistaNeurobiology of Disease
Volume86
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Animals
  • Behavior, Animal
  • Bidirectional synaptic plasticity
  • Corpus Striatum
  • Dyskinesia, Drug-Induced
  • Levodopa
  • Levodopa treatment
  • MAP Kinase Signaling System
  • Male
  • Motor Activity
  • Neuronal Plasticity
  • Neurons
  • Oxidopamine
  • Parkinson's disease animal models
  • Parkinsonian Disorders
  • Piperazines
  • Rats
  • Rats, Wistar
  • Serotonergic transmission
  • Serotonin Receptor Agonists
  • Synapses
  • Synaptic Transmission
  • TOR Serine-Threonine Kinases

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