22 December 2010
Picconi B, Bagetta V,
Ghiglieri V, Paillè V, Di Filippo M, Pendolino V, Tozzi A, Giampà C, Fusco FR,
Sgobio C, Calabresi P
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.
