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

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.

• Authors: Barbara Picconi, Vincenza Bagetta, Veronica Ghiglieri, Vincent Paillè, Massimiliano Di Filippo, Valentina Pendolino, Alessandro Tozzi, Carmela Giampà, Francesca R Fusco, Carmelo Sgobio, Paolo Calabresi
• Journal: Brain : a journal of neurology (Brain) Vol. 134 Issue Pt 2 Pg. 375-87 (Feb 2011) ISSN: 1460-2156 [Electronic] England
• PMID: 21183486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase Inhibitors
• Piperazines
• Purinones
• Pyrimidinones
• UK 343,664
• Levodopa
• Oxidopamine
• zaprinast
• Cyclic GMP

Topics

• Animals
• Corpus Striatum (drug effects, enzymology, physiology)
• Cyclic GMP (pharmacology, physiology)
• Dyskinesia, Drug-Induced (drug therapy, enzymology)
• Levodopa (adverse effects)
• Long-Term Synaptic Depression (drug effects, physiology)
• Male
• Microinjections
• Neurons (physiology)
• Oxidopamine
• Parkinsonian Disorders (chemically induced, physiopathology)
• Phosphodiesterase Inhibitors (administration & dosage, pharmacology)
• Piperazines (pharmacology)
• Purinones (pharmacology)
• Pyrimidinones (pharmacology)
• Rats
• Rats, Wistar