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Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

Original publication

DOI

10.1172/JCI71640

Type

Journal article

Journal

J Clin Invest

Publication Date

03/2014

Volume

124

Pages

1340 - 1349

Keywords

Aged, Antiparkinson Agents, Buspirone, Case-Control Studies, Dopamine, Double-Blind Method, Dyskinesia, Drug-Induced, Female, Humans, Levodopa, Male, Middle Aged, Parkinson Disease, Putamen, Raclopride, Radionuclide Imaging, Radiopharmaceuticals, Serotonergic Neurons, Serotonin 5-HT1 Receptor Agonists, Synapses, Treatment Outcome