Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia

N. Nevalainen; S. Af Bjerkén; G. A. Gerhardt; I. Strömberg

doi:10.1016/j.neuroscience.2013.12.029

Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia

N. Nevalainen
, S. Af Bjerkén
, G. A. Gerhardt
, I. Strömberg

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (~30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT_1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.

Original language	English
Pages (from-to)	73-86
Number of pages	14
Journal	Neuroscience
Volume	260
DOIs	https://doi.org/10.1016/j.neuroscience.2013.12.029
State	Published - Feb 28 2014

Bibliographical note

Funding Information:
This study was funded by the Swedish Research Council Grant # 09917, The Umeå University Medical Faculty Funds, Konung Gustav V och drottning Victoria’s Fond, and Parkinsonfonden, Sweden. There are no conflicts of interest to be declared, neither financial nor personal.

Funding

This study was funded by the Swedish Research Council Grant # 09917, The Umeå University Medical Faculty Funds, Konung Gustav V och drottning Victoria’s Fond, and Parkinsonfonden, Sweden. There are no conflicts of interest to be declared, neither financial nor personal.

Funders	Funder number
Konung Gustav V och drottning Victoria’s Fond
The Umeå University Medical Faculty Funds
Vetenskapsrådet	09917
Vetenskapsrådet

Keywords

5-HT
Dyskinesia
Fluoxetine
In vivo chronoamperometry
L-DOPA
WAY-100 635

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuroscience.2013.12.029

Cite this

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title = "Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia",

abstract = "The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (\textasciitilde{}30\%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.",

keywords = "5-HT, Dyskinesia, Fluoxetine, In vivo chronoamperometry, L-DOPA, WAY-100 635",

author = "N. Nevalainen and \{Af Bjerk{\'e}n\}, S. and Gerhardt, \{G. A.\} and I. Str{\"o}mberg",

note = "Funding Information: This study was funded by the Swedish Research Council Grant \# 09917, The Ume{\aa} University Medical Faculty Funds, Konung Gustav V och drottning Victoria{\textquoteright}s Fond, and Parkinsonfonden, Sweden. There are no conflicts of interest to be declared, neither financial nor personal.",

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AU - Af Bjerkén, S.

AU - Gerhardt, G. A.

AU - Strömberg, I.

N1 - Funding Information: This study was funded by the Swedish Research Council Grant # 09917, The Umeå University Medical Faculty Funds, Konung Gustav V och drottning Victoria’s Fond, and Parkinsonfonden, Sweden. There are no conflicts of interest to be declared, neither financial nor personal.

PY - 2014/2/28

Y1 - 2014/2/28

N2 - The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (~30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.

AB - The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (~30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.

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KW - Dyskinesia

KW - Fluoxetine

KW - In vivo chronoamperometry

KW - L-DOPA

KW - WAY-100 635

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DO - 10.1016/j.neuroscience.2013.12.029

M3 - Article

C2 - 24361918

AN - SCOPUS:84891960316

SN - 0306-4522

VL - 260

SP - 73

EP - 86

JO - Neuroscience

JF - Neuroscience

ER -

Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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