title: 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.affiliation: Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Bagetta
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.forename: Vincent
authors.initials: V
authors.lastname: Paillè
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Fusco
authors.forename: Carmelo
authors.initials: C
authors.lastname: Sgobio
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D006152:Cyclic GMP / Q000494:pharmacology / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000201:enzymology*; D007980:Levodopa / Q000009:adverse effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011688:Purinones; D011744:Pyrimidinones; C450961:UK 343,664; D007980:Levodopa; D016627:Oxidopamine; C011145:zaprinast; D006152:Cyclic GMP