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The Roles of Striatal Serotonin and l-Amino-acid Decarboxylase on l-DOPA-induced Dyskinesia in a Hemiparkinsonian Rat Model

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Abstract

The administration of l-DOPA is the standard treatment for Parkinson’s disease (PD). However, the symptomatic relief provided by long-term administration may be compromised by l-DOPA-induced dyskinesia (LID) that presents as adverse fluctuations in motor responsiveness and progressive loss of motor control. In the later stages of PD, raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine (DA) neurons by converting and releasing DA derived from exogenous l-DOPA. Since the serotonin system does not have an autoregulatory mechanism for DA, raphe-mediated striatal DA release may fluctuate dramatically and precede the development of LID. The 6-hydroxydopamine lesioned rats were treated with l-DOPA (6 mg/kg) and benserazide (15 mg/kg) daily for 3 weeks to allow for the development of abnormal involuntary movement score (AIMs). In rats with LID, chronic treatment with l-DOPA increased striatal DA levels compared with control rats. We also observed a relative increase in the expression of striatal l-amino-acid decarboxylase (AADC) in LID rats, even though tyrosine hydroxylase (TH) expression did not increase. The administration of l-DOPA also increased striatal serotonin immunoreactivity in LID rats compared to control rats. Striatal DA and 5-hydroxytryptamine (5-HT) levels were negatively correlated in l-DOPA-treated rats. These results of this study reveal that 5-HT contributes to LID. Striatal DA positively influences LID, while 5-HT is negatively associated with LID. Finally, we suggest that by strategic modification of the serotonin system it may be possible to attenuate the adverse effects of chronic l-DOPA therapy in PD patients.

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Acknowledgments

This study was supported by a grant from the Korea Science and Engineering Foundation (2009-0091460) through the MRC for Regulation of Stem Cell Behaviors at Hanyang University College of Medicine, Republic of Korea, and by a grant (SC-3140) from the Stem Cell Research Center of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology, Republic of Korea.

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Authors and Affiliations

  1. Department of Microbiology, College of Medicine, Hanyang University, 133-791, Seoul, Korea

    Changhwan Park

  2. Department of Pharmacology, College of Medicine, Hanyang University, 133-791, Seoul, Korea

    Sukju Gil, Jeongeun Lee & Hyunchul Koh

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  1. Sukju Gil
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  2. Changhwan Park
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  3. Jeongeun Lee
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  4. Hyunchul Koh
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Correspondence to Hyunchul Koh.

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Sukju Gil and Changhwan Park contributed equally to this work.

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Gil, S., Park, C., Lee, J. et al. The Roles of Striatal Serotonin and l-Amino-acid Decarboxylase on l-DOPA-induced Dyskinesia in a Hemiparkinsonian Rat Model. Cell Mol Neurobiol 30, 817–825 (2010). https://doi.org/10.1007/s10571-010-9509-9

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  • DOI: https://doi.org/10.1007/s10571-010-9509-9

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