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Effects of Prolonged Selective Serotonin Reuptake Inhibition on the Development and Expression of L-DOPA-induced Dyskinesia in Hemi-Parkinsonian Rats

Effects of Prolonged Selective Serotonin Reuptake Inhibition on the Development and Expression of L-DOPA-induced Dyskinesia in Hemi-Parkinsonian Rats

Melissa M Conti, Corinne Y Ostock, David Lindenbach, Adam A Goldenberg, Elias Kampton, Rich Dell'isola, Aaron C Katzman, Christopher Bishop

Neuropharmacology. 2014 Feb;77:1-8.

PMID: 24067924

Abstract:

Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and -naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT(1A) receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP64006446	Paroxetine maleate salt		64006-44-6	Price

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