RGD Reference Report - Calcium-permeable AMPA receptors are involved in the induction and expression of l-DOPA-induced dyskinesia in Parkinson's disease. - Rat Genome Database

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

Authors: Kobylecki, C  Cenci, MA  Crossman, AR  Ravenscroft, P 
Citation: Kobylecki C, etal., J Neurochem. 2010 Jul;114(2):499-511. doi: 10.1111/j.1471-4159.2010.06776.x. Epub 2010 Apr 28.
RGD ID: 10003039
Pubmed: PMID:20456008   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2010.06776.x   (Journal Full-text)

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 Ca(2+)-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca(2+)-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 Ca(2+)-permeable AMPA receptors are critically involved in both the induction and subsequent expression of LID, and represent a potential target for anti-dyskinetic therapies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Drug-Induced Dyskinesia  ISOPenk (Rattus norvegicus)10003039; 10003039mRNA:increased expression:brain:striatum:RGD 
Drug-Induced Dyskinesia  IEP 10003039mRNA:increased expression:brain:striatum:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Penk  (proenkephalin)

Genes (Mus musculus)
Penk  (preproenkephalin)

Genes (Homo sapiens)
PENK  (proenkephalin)


Additional Information