¹Laboratoire de Neurobiologie de la Cognition, CNRS and Université de Provence, Marseille cedex, France

Correspondence: M Amalric, Laboratoire de Neurobiologie de la Cognition, CNRSUMR 615531, chemin Joseph Aiguier 13402, Marseille cedex 20, France. Tel.: +33 4 91 16 42 66; Fax +33 4 91 77 50 83; E-mail: amalric@lncf.cnrs-mrs.fr

Received 10 October 2003; Revised 18 February 2004; Accepted 19 February 2004; Published online 24 March 2004.

Abstract

Recent evidence suggest that antagonism of adenosine A_2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A_2A 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, A_2A 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 A_2A and mGlu₅ receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.