Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Feb:77:1-8.
doi: 10.1016/j.neuropharm.2013.09.017. Epub 2013 Sep 22.

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

Melissa M Conti  1 , Corinne Y Ostock  2 , David Lindenbach  3 , Adam A Goldenberg  4 , Elias Kampton  5 , Rich Dell'isola  6 , Aaron C Katzman  7 , Christopher Bishop  8
Affiliations

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

Melissa M Conti et al. Neuropharmacology. 2014 Feb.

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.

Keywords: 3,4-dihydroxyphenylacetic acid; 5-HIAA; 5-HT; 5-HT(1A) receptor; 5-hydroxyindoleacetic acid; 6-OHDA; 6-hydroxydopamine; AIMs; ALO; Abnormal involuntary movements; Axial, limb and orolingual; Benserazide; DA; DAT; DL-serine 2-(2,3,4-trihydroxybenzyl) hydrazine hydrochloride; DMSO; DOPAC; Dimethyl sulfoxide; Dopamine; Dopamine transporter; FAS; Forepaw adjusting steps test; HPLC; High performance liquid chromatography; LID; MFB; Medial forebrain bundle; N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; NE; Norepinephrine; PD; Parkinson's disease; SERT; SSRI; Selective 5-HT reuptake inhibitor; Selective serotonin reuptake inhibitor; Serotonin; Serotonin transporter; WAY100635; l-DOPA-induced dyskinesia.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Effects of prolonged selective 5-HT reuptake inhibitors citalopram (A) and paroxetine (B) on the expression of established L-DOPA-induced abnormal involuntary movements (AIMs). Rats were L-DOPA-primed for 14 days and axial, limb, and orolingual (ALO) AIMs were recorded on days Prime 8 and Prime 14. Thereafter, equally dyskinetic groups were treated with vehicle, citalopram (3 or 5 mg/kg, s.c.), or paroxetine (0.5 or 1.25 mg/kg, s.c.) 30 min prior to L-DOPA (6 mg/kg, s.c.) + benserazide (15 mg/kg, s.c.) daily for 22 days. The arrow indicates the start of SSRI and L-DOPA co-treatment. ALO AIMs were evaluated for 3 h after L-DOPA on days 15, 22, 29, and 36. Values are expressed as medians (AIMs ± median absolute difference; M.A.D.). Significant differences were determined by non-parametric Kruskal-Wallis ANOVAs at each test day with Mann-Whitney post-hocs. * p < 0.05 vs. Vehicle + L-DOPA, + p < 0.05 vs. Citalopram (3) or Paroxetine (0.5) + L-DOPA.
Fig. 2
Fig. 2
Effects of prolonged selective 5-HT reuptake inhibitors citalopram and paroxetine on L-DOPA reversal of motor deficit on the forepaw adjustment steps test. Baseline stepping deficits were established 3 weeks post-lesion, prior to L-DOPA priming. Rats then received daily treatment with vehicle, citalopram (3 or 5 mg/kg, s.c.), or paroxetine (0.5 or 1.25 mg/kg, s.c.) 30 min prior to L-DOPA (6 mg/kg, s.c.) + benserazide (15 mg/kg, s.c.) for 22 days. Forepaw adjusting steps were evaluated 60 min after treatments on days 17, 24, and 31. Values (as means + standard mean error; S.E.M.) are expressed as percent intact vs. intact forepaw. Significant differences were determined by 1-way ANOVAs within each treatment condition. When appropriate, motor performance differences across test days were analyzed with Fisher LSD post-hocs. Baseline values were evaluated by a 1-way ANOVA to determine equivalent stepping deficit across groups. * p < 0.05 vs. Baseline, ^ p < 0.05 vs. Day 17, + p < 0.05 vs. Day 24.
Fig. 3
Fig. 3
Effects of prolonged selective 5-HT reuptake inhibitors citalopram (A) and paroxetine (B) on the development of L-DOPA-induced abnormal involuntary movements (AIMs). L-DOPA-naïve rats were treated with vehicle, citalopram (3 or 5 mg/kg, s.c.), or paroxetine (0.5 or 1.25 mg/kg, s.c.) 30 min prior to vehicle or L-DOPA (6 mg/kg, s.c.) + benserazide (15 mg/kg, s.c.) daily for 22 days. ALO AIMs were evaluated for 3 h after L-DOPA on days 1, 8, 15, and 22. Values are expressed as medians (AIMs + median absolute difference; M.A.D.). Significant differences were determined by non-parametric Kruskal-Wallis ANOVAs at each test day with Mann-Whitney post-hocs. * p < 0.05 vs. Vehicle + L-DOPA, + p < 0.05 vs. Citalopram (5) or Paroxetine (1.25) + L-DOPA.
Fig. 4
Fig. 4
Effects of prolonged selective 5-HT reuptake inhibitors citalopram and paroxetine on L-DOPA reversal of motor deficit in L-DOPA-naïve rats using the forepaw adjustment steps test. Baseline stepping deficits were established 3 weeks post-lesion. Rats then received daily treatment with vehicle, citalopram (3 or 5 mg/kg, s.c.), or paroxetine (0.5 or 1.25 mg/kg, s.c.) 30 min prior to L-DOPA (6 mg/kg, s.c.) + benserazide (15 mg/kg, s.c.) for 22 days. Forepaw adjusting steps were evaluated 60 min after treatments on days 3, 10, and 17. Values (as means + standard mean error; S.E.M.) are expressed as percent intact vs. intact forepaw. Significant differences were evaluated by 1-way ANOVAs for baseline stepping across groups and within each treatment condition. When appropriate, motor performance differences across test days were analyzed with Fisher LSD post-hocs. * p < 0.05 vs. Baseline, + p < 0.05 vs. Sham-Vehicle.
Fig. 5
Fig. 5
Effects of the 5-HT1A receptor antagonist WAY100635 on the anti-dyskinetic effects of selective 5-HT reuptake inhibitors citalopram (A) and paroxetine (B). Rats were L-DOPA-primed for 14 days and ALO AIMs were recorded on days 1, 8, and 14. Rats were then treated with vehicle or WAY100635 (0.5, s.c.) 5 min before vehicle, citalopram (3 or 5 mg/kg, s.c.), or paroxetine (0.5 or 1.25 mg/kg, s.c.) which was given 30 min prior to L-DOPA (6 mg/kg, s.c.) + benserazide (15 mg/kg, s.c.) each test day. ALO AIMs were evaluated for 3 h after L-DOPA. Values are expressed as medians (AIMs + median absolute difference; M.A.D.). Significant differences were determined by non-parametric Friedman ANOVAs and Wilcoxon post-hocs. * p < 0.05 vs. Vehicle + L-DOPA, ^ p < 0.05 vs. WAY + L-DOPA, + p < 0.05 vs. Citalopram (3) or Paroxetine (0.5) + L-DOPA, % p < 0.05 vs. Citalopram (5) or Paroxetine (1.25) + L-DOPA.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Arai R, Karasawa N, Geffard M, Nagatsu I. L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluoresence study. Neurosci Lett. 1995;195:195–198. - PubMed
    1. Bara-Jiminez W, Bibbiani F, Morris M, Dimitrova T, Sherzai A, Mouradian M, Chase T. Effects of serotonin 5-HT1A agonist in advanced Parkinson’s disease. Mov Disord. 2005;20:932–936. - PubMed
    1. Benmansour S, Owens W, Cecchi M, Morilak D, Frazer A. Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci. 2002;22:6766–6772. - PMC - PubMed
    1. Bibbiani F, Oh J, Chase T. Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurol. 2001;57:1829–1834. - PubMed
    1. Bishop C, George J, Buchta W, Goldenberg A, Mohamed M, Dickinson S, Eissa S, Eskow Jaunarajs K. Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats. Eur J Neurosci. 2012;36:2839–2848. - PMC - PubMed

Publication types

MeSH terms