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Calcium-permeable AMPA receptors are involved in the induction and expression of l-DOPA-induced dyskinesia in Parkinson's disease

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Author

Summary, in English

P>Overactivity of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is implicated in the pathophysiology of l-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we evaluated the behavioural and molecular effects of acute and chronic blockade of Ca2+-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca2+-permeable AMPA receptor antagonist 1-trimethylammonio-5-(1-adamantane-methylammoniopentane) dibromide hydrobromide (IEM 1460) on abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat and LID in the MPTP-lesioned non-human primate were assessed. Subsequently, the effects of chronic treatment of 6-OHDA-lesioned rats with vehicle, l-DOPA/benserazide (6/15 mg/kg, i.p.) + vehicle or l-DOPA + IEM 1460 (3 mg/kg, i.p.) on behavioural and molecular correlates of priming for LID were evaluated. In the 6-OHDA-lesioned rat and MPTP-lesioned non-human primate, acute treatment with IEM 1460 (1-3 mg/kg) dose-dependently reduced LID without adverse effects on motor performance. Chronic co-treatment for 21 days with IEM 1460 reduced the induction of AIMs by l-DOPA in the 6-OHDA-lesioned rat without affecting peak rotarod performance, and attenuated AIMs score by 75% following l-DOPA challenge (p < 0.05). Chronic IEM 1460 treatment reversed l-DOPA-induced up-regulation of pre-proenkephalin-A, and normalised pre-proenkephalin-B mRNA expression in the lateral striatum, indicating an inhibition of both behavioural and molecular correlates of priming. These data suggest that Ca2+-permeable AMPA receptors are critically involved in both the induction and subsequent expression of LID, and represent a potential target for anti-dyskinetic therapies.

Publishing year

2010

Language

English

Pages

499-511

Publication/Series

Journal of Neurochemistry

Volume

114

Issue

2

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Neurosciences

Keywords

  • Parkinson's disease
  • l-DOPA-induced dyskinesia
  • glutamate
  • calcium
  • animal models
  • alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Status

Published

Research group

  • Basal Ganglia Pathophysiology

ISBN/ISSN/Other

  • ISSN: 1471-4159