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

J. Neurochem. (2010) 114 , 409–511. Abstract Overactivity of striatal α‐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.