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

Abstract

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 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.

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

“…We show that LID in absence of a transplant can be reduced using a selection of pharmacological agents, confirming previous findings (Kobylecki et al, 2010;Lundblad et al, 2002;Monville et al, 2005;Morgese et al, 2007;Munoz et al, 2008;Paquette et al, 2010). Conversely, D 3 receptor antagonism, m opioid receptor antagonism, CB1 cannabinoid agonism and adrenergic receptor antagonism has little effect on amphetamine generated AIMs.…”

“…Drugs and corresponding doses were identified on their proficiency to ameliorate AIMs elicited in response to L-DOPA in reports from the literature (Kobylecki et al, 2010;Lundblad et al, 2002Lundblad et al, , 2005Monville et al, 2005;Morgese et al, 2007;Munoz et al, 2008;Paquette et al, 2010;Rylander et al, 2010Rylander et al, , 2009). The agents were administered prior to 2.5 mg/kg of methamphetamine and AIMs scored over 3 h post injection.…”

Rebalance of Striatal NMDA/AMPA Receptor Ratio Underlies the Reduced Emergence of Dyskinesia During D2-Like Dopamine Agonist Treatment in Experimental Parkinson's Disease

“…In accordance with our results, a recent paper from Kobylecki et al (2010), using a selective GluR2-lacking AMPAR antagonist (IEM-1460), which was able to significantly reduce the induction and expression of dyskinesia, revealed the pivotal role of these receptors in LID induction and expression.…”

New Approaches to Therapy

“…As a consequence, the focus of research has been broadened to other classes of glutamatergic receptor and to the AMPA receptor (Bibbiani et al, 2005;Kobylecki et al, 2010;Perier et al, 2002). Within the striatum of rodent and primate models of LID, AMPA receptors are abnormally phosphorylated and appear to have increased targeting to the synapse (Silverdale et al, 2010).…”

“…The cortico-striate pathway has been shown to be altered following AIMs induction in 6-OHDA-lesioned rats with alterations in LTD and abnormal storage of information (Cenci and Konradi, 2010;Kobylecki et al, 2010). Since it activates glutamatergic receptors on medium spiny neurones making up the direct and indirect pathways, this may be a key target.…”