Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats

NEUROPHARMACOLOGY

卷:77

Article

Conti, Melissa M.¹  Ostock, Corinne Y.¹  Lindenbach, David¹  Goldenberg, Adam A.¹  Kampton, Elias¹  Dell'isola, Rich¹  Katzman, Aaron C.¹  Bishop, Christopher¹ 

[1] Binghamton Univ, Dept Psychol, Behav Neurosci Program, Binghamton, NY 13902 USA

关键词: Abnormal involuntary movements;    Dopamine;    Serotonin transporter;    Parkinson's disease;    Selective serotonin reuptake inhibitor;    5-HT1A receptor;   

DOI  :  10.1016/j.neuropharm.2013.09.017

来源: Elsevier

【 摘 要 】

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 -naive 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-HT1A receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naive 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-HT1A receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels. (C) 2013 Elsevier Ltd. All rights reserved.

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