Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia.
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.


CONCLUSIONS
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.
Rylander
Daniella
D
Basal Ganglia Pathophysiology Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden. daniella.rylander@med.lu.se
Parent
Martin
M
O'Sullivan
Sean S
SS
Dovero
Sandra
S
Lees
Andrew J
AJ
Bezard
Erwan
E
Descarries
Laurent
L
Cenci
M Angela
MA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000368:Aged; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000473:pathology*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine