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

Brain. 2011 Feb;134(Pt 2):375-87. doi: 10.1093/brain/awq342. Epub 2010 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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