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

Abstract

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.

• Authors: Christopher Kobylecki, M Angela Cenci, Alan R Crossman, Paula Ravenscroft
• Journal: Journal of neurochemistry (J Neurochem) Vol. 114 Issue 2 Pg. 499-511 (Jul 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20456008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Enkephalins
• IEM 1460
• Protein Precursors
• Receptors, AMPA
• Levodopa
• Benserazide
• Oxidopamine
• preproenkephalin
• Adamantane
• Calcium

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Antiparkinson Agents (adverse effects)
• Behavior, Animal (drug effects)
• Benserazide (adverse effects)
• Brain (drug effects, metabolism)
• Calcium (metabolism)
• Callithrix
• Dyskinesia, Drug-Induced (etiology, metabolism, psychology)
• Enkephalins (biosynthesis)
• Levodopa (adverse effects)
• Male
• Motor Activity (drug effects)
• Oxidopamine
• Parkinson Disease (drug therapy, etiology, metabolism)
• Protein Precursors (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Receptors, AMPA (antagonists & inhibitors, physiology)