Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia.
Ann Neurol.. 2010-09-29; 68(5): 619-628
DOI: 10.1002/ana.22097
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1. Ann Neurol. 2010 Nov;68(5):619-28. doi: 10.1002/ana.22097.
Maladaptive plasticity of serotonin axon terminals in levodopa-induced
dyskinesia.
Rylander D(1), Parent M, O’Sullivan SS, Dovero S, Lees AJ, Bezard E, Descarries
L, Cenci MA.
Author information:
(1)Basal Ganglia Pathophysiology Laboratory, Department of Experimental Medical
Science, Lund University, Lund, Sweden.
Comment in
Ann Neurol. 2010 Nov;68(5):578-80.
OBJECTIVE: Striatal serotonin projections have been implicated in
levodopa-induced dyskinesia by providing an unregulated source of dopamine
release. We set out to determine whether these projections are affected by
levodopa treatment in a way that would favor the occurrence of dyskinesia.
METHODS: As an index of terminal serotonin innervation density, we measured
radioligand binding to the plasma membrane serotonin transporter (SERT) in
levodopa-treated dyskinetic and nondyskinetic subjects, using brain tissue from
both rat and monkey models of Parkinson disease as well as parkinsonian patients.
In addition, striatal tissue from dyskinetic rats was used for morphological and
ultrastructural analyses of serotonin axon terminals, and for studies of
stimulated [³H]dopamine release.
RESULTS: Across all conditions examined, striatal levels of SERT radioligand
binding were significantly elevated in dyskinetic subjects compared to
nondyskinetic cases. In the rat striatum, dyskinesiogenic levodopa treatment had
induced sprouting of serotonin axon varicosities having a relatively high
synaptic incidence. This response was associated with increased
depolarization-induced [³H]dopamine release and with a stronger release
potentiation by brain-derived neurotrophic factor.
INTERPRETATION: This study provides the first evidence that L-dopa treatment
induces sprouting of serotonin axon terminals, with an increased incidence of
synaptic contacts, and a larger activity-dependent potentiation of dopamine
release in the dopamine-denervated striatum. Treatment-induced plasticity of the
serotonin innervation may therefore represent a previously unappreciated cause of
altered dopamine dynamics. These results are important for understanding the
mechanisms by which L-dopa pharmacotherapy predisposes to dyskinesia, and for
defining biomarkers of motor complications in Parkinsons disease.
DOI: 10.1002/ana.22097
PMID: 20882603 [Indexed for MEDLINE]