The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.

Picconi, B., Bagetta, V., Ghiglieri, V., Paillè, V., Di Filippo, M., Pendolino, V., Tozzi, A., Giampa', C., Fusco, F., Sgobio, C., Calabresi, P., Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia, <<BRAIN>>, 2011; 134 (Pt 2): 375-387. [doi:10.1093/brain/awq342] [http://hdl.handle.net/10807/57489]

Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia

Giampa', Carmela;Calabresi, Paolo
2011

Abstract

The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.
2011
Inglese
Picconi, B., Bagetta, V., Ghiglieri, V., Paillè, V., Di Filippo, M., Pendolino, V., Tozzi, A., Giampa', C., Fusco, F., Sgobio, C., Calabresi, P., Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia, <<BRAIN>>, 2011; 134 (Pt 2): 375-387. [doi:10.1093/brain/awq342] [http://hdl.handle.net/10807/57489]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/57489
Citazioni
  • ???jsp.display-item.citation.pmc??? 44
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact