Abstract
Recent evidence suggest that antagonism of adenosine A2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A2A and the glutamate subtype 5 metabotropic receptors (mGlu5) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A2A and mGlu5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A2A and mGlu5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.
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Acknowledgements
This research was supported by the Centre National de la Recherche Scientifique, the Fondation de France (MA) and a franco-italian Galilée program by the Ministère des Affaires Etrangères and the CRUI. RC was supported by the CNR (Italy) and NB by the Fondation pour la Recherche Medicale and Institut Lilly. The authors are grateful to Dr Fabrizio Gasparini (Novartis Pharma AG, Basel, Switzerland) for the generous gift of MPEP.
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Coccurello, R., Breysse, N. & Amalric, M. Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats. Neuropsychopharmacol 29, 1451–1461 (2004). https://doi.org/10.1038/sj.npp.1300444
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