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Comparative Effects of Acute or Chronic Administration of Levodopa to 6-OHDA-lesioned Rats on the Expression and Phosphorylation of N-methyl-d-aspartate Receptor NR1 Subunits in the Striatum

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Abstract

N-methyl-d-aspartate receptor (NMDA) has been increasingly implicated in the formation and maintenance of various forms of behavioral and synaptic plasticity. Recent evidence has linked striatal NMDA function to the adverse effects of long-term dopaminergic treatment in Parkinson’s disease. The subcellular distribution and phosphorylation of NMDA subunit, NR1, reflects NMDA receptor activity. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa treatment of parkinsonian patients, we evaluated the effects of unilateral nigrostriatal depletion with 6-hydroxydopamine and subsequent levodopa treatment on motor responses and NR1 alterations. Three weeks of levodopa administration to rats shortened the rotational duration and increased the peak turning responses, which lasted after withdrawal of chronic levodopa treatment. We found a significant reduction in the abundance of both phosphorylated NR1 on serine residues 890 and 896 (pNR1S890 and pNR1S896) and NR1 in the cell plasma membrane of lesioned striatum. Chronic treatment of lesioned rats with levodopa markedly upregulated pNR1S890, pNR1S896, and pNR1S897 in lesioned striatum with a concomitant normalization of the plasma membrane NR1 abundance. The magnitude of increased pNR1S890, pNR1S896, and pNR1S897 is dependent on the number of levodopa injections and is paralleled by a sensitization of the rotational response. Our data indicate that glutamate signaling is triggered during the levodopa administration. Activated NMDA receptor NR1-mediated mechanisms are involved in the persistent expression of the motor response alterations that appear during chronic levodopa therapy of parkinsonian rats and continue after treatment withdrawal.

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Acknowledgments

This study was supported by the Project Sponsored by the Shanghai Pujiang Program, Shanghai-Philips Research and Development Funds, Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry and the Post-Project of Excellent Young Medical Person of Xihhua Hospital of Shanghai, China.

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  1. Maowen Ba

    Present address: Department of Neurology, Yuhuangding Hospital Affiliated to Qingdao Medical University, 264000, Shandong, People’s Republic of China

Authors and Affiliations

  1. Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, People’s Republic of China

    Min Kong, Maowen Ba, Lu Song & Zhenguo Liu

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  1. Min Kong
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  2. Maowen Ba
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  3. Lu Song
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Correspondence to Zhenguo Liu.

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M. Kong and M. Ba are contributed equally to this work.

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Kong, M., Ba, M., Song, L. et al. Comparative Effects of Acute or Chronic Administration of Levodopa to 6-OHDA-lesioned Rats on the Expression and Phosphorylation of N-methyl-d-aspartate Receptor NR1 Subunits in the Striatum. Neurochem Res 34, 1513–1521 (2009). https://doi.org/10.1007/s11064-009-9939-2

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  • DOI: https://doi.org/10.1007/s11064-009-9939-2

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