Serotonin transporter inhibition attenuates l‐DOPA‐induced dyskinesia without compromising l‐DOPA efficacy in hemi‐parkinsonian rats

Abstract

Long-term dopamine replacement therapy with l-DOPA in Parkinson's disease often leads to the development of abnormal involuntary movements known as l-DOPA-induced dyskinesia. Growing evidence suggests that, following dopamine cell loss, serotonin neurons acting as surrogates for dopaminergic processes take up l-DOPA, convert it to dopamine and release it in an unregulated fashion that precipitates dyskinesia. Although most studies have focused on serotonin 5-HT(1) receptor stimulation as an antidyskinetic strategy, targeting the serotonin transporter modulation of dopamine activity has been overlooked. Therefore, in the current study, selective serotonin reuptake inhibitors were tested for their ability to reduce l-DOPA- and apomorphine-induced dyskinesia. In Experiments 1 and 2, hemi-parkinsonian rats were primed with l-DOPA until stable dyskinesia developed. Rats in Experiment 1 were administered the selective serotonin reuptake inhibitors paroxetine, citalopram or fluoxetine, followed by l-DOPA. Abnormal involuntary movements and forepaw adjusting steps were recorded to determine the effects of these compounds on dyskinesia and motor performance, respectively. Brains were collected on the final test day, after which striatal and raphe monoamines were examined via high-performance liquid chromatography. In Experiment 2, dyskinesias were measured after selective serotonin reuptake inhibitors and apomorphine. Serotonin reuptake inhibitors dose-dependently attenuated l-DOPA- but not apomorphine-induced dyskinesia, and preserved l-DOPA efficacy. Neurochemically, serotonin transporter inhibition enhanced striatal and raphe serotonin levels and reduced its turnover, indicating a potential mechanism of action. The present results support targeting serotonin transporters to improve Parkinson's disease treatment and provide further evidence for the role of the serotonin system in l-DOPA's effects.