In vivo antiparkinson activity of drugs acting on A(2A)-CB1-D-2 receptors

PINNA A;COSTA G;ARMENTERO M. T;MULLER C. E;FRANCO R;SIMOLA N.

2012-01-01

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Abstract

Objective: To investigate the in vivo anti-parkinsonian activity of a new drug combination interacting with the adenosine A2A receptor (A2AR), cannabinoid CB1 receptor (CB1R) and dopamine D2 receptor (D2R) heteromers in rodent models of Parkinson’s disease (PD). Background: Experimental and clinical data have indicated that adenosine A2AR antagonists can provide symptomatic improvement by potentiating the effect of L-DOPA without worsening dyskinesia, and therefore represent an alternative therapeutic target for drug development in PD. The existence of functional interactions between A2AR and CB1R receptors in striatum have been reported. Moreover, some data demonstrated that A2AR, CB1R and D2R form G protein-coupled receptor heteromers in cotransfected cells and in rat striatum. Methods: The CB1R antagonist rimonabant, and the A2AR antagonists (MSX-3 or SCH58261) were administered singularly or in combination with a sub-threshold dose of L-DOPA (3 mg/kg) in two model of PD: 1) parkinsonian tremulous jaw movements induced by the acethylcholinesterase inhibitor tacrine; 2) contralateral turning behaviour in rats bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigrostriatal pathway. Results: Neither rimonabant (1 mg/kg) alone nor the combined administration of rimonabant and MSX-3, or SCH58261, significantly counteracted tremulous jaw movements induced by tacrine. Moreover, in 6-OHDA-lesioned rats, administration of rimonabant and MSX-3, or SCH58261, singularly or in combination did not induce any contralateral turning. Rimonabant (1 mg/kg) did not increase contralateral turning induced by L-DOPA (3 mg/kg), whereas administration of either A2AR antagonists, MSX-3 or SCH58261, did increase contralateral turns induced by L-DOPA. However, the combined administration of rimonabant and MSX-3, or SCH58261, with L-DOPA did not further increase contralateral turns respect to that induced by the A2AR antagonists. Conclusions: Taken together these results suggest that CB1R blockade does not seem to influence positively the antiparkinsonian effects of A2AR antagonists.