[imark3000]

Targeting Serotonin Transporters for the Treatment of L-DOPA-induced Dyskinesia
https://www.michaeljfox.org/foundati...p?grant_id=880
Preliminary findings from our laboratory had suggested that the FDA-approved anti-depressants and selective serotonin reuptake inhibitors (SSRIs) citalopram and paroxetine acutely reduced L-DOPA-induced dyskinesia (LID) in a pre-clinical model of Parkinson’s disease (PD). In the first year of support through The Michael J. Fox Foundation’s Dyskinesia Challenge Program, we have been able to significantly extend these findings. Our first recently completed experiment demonstrated that the potent anti-dyskinetic effects of SSRIs, given as an interventional strategy, were maintained over several weeks and did not come at the expense of L-DOPA’s anti-parkinsonian efficacy. Preliminary findings from our second experiment, examining the protective effects of SSRIs on the development of LID are yielding complimentary results; that administering SSRIs prior to LID development delays or attenuates its expression. Collectively, our pre-clinical findings thus far implicate the translational potential of SSRIs for the treatment of LID for the PD patient.
Imad

[imark3000]

Serotonin transporter inhibition attenuates L-DOPA-induced dyskinesia without compromising L-DOPA efficacy in hemi-parkinsonian rats

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445783/
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. While most studies have focused on serotonin 5-HT1 receptor stimulation as an anti-dyskinetic strategy, targeting 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, while preserving 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.