Antiparkinson activity of drugs acting on D2-CB1-A2A receptors

To date the most effective therapy in Parkinson's disease (PD) is treatment with L-3,4-dihydroxyphenylalanine (L-DOPA). However, long-term L-DOPA therapy is associated with motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor (A2AR) antagonists can provide symptomatic improvement by potentiating the effect of L-DOPA and minimizing side effects, and therefore represent an alternative therapeutic target for drug development in PD. Several studies have reported the existence of functional interactions between adenosine A2AR and cannabinoid CB1 (CB1R) or dopamine D2 (D2R) receptors in striatum. Moreover, some data demonstrated that A2AR, CB1R and D2R may form G protein-coupled receptor heteromers in cotransfected cells and in rat striatum. On this basis, we investigated the in vivo antiparkinsonian activity of a new drug combination interacting with these heteromers in PD rat models. The CB1R antagonist (rimonabant), and the adenosine A2AR antagonists (MSX-3 or SCH 58261) were administered singularly or in combination with a sub-threshold dose of L-DOPA (3 mg/kg) in two models of PD: 1) contralateral turning behavior in rats bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigrostriatal pathway; 2) tremulous jaw movements induced by tacrine, a validated model of parkinsonian tremor. 6-OHDA-lesioned rats treated with rimonabant and MSX-3, or SCH 58261, alone or in combination did not show 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 (3 mg/kg) or SCH 58261 (3 mg/kg), did increase contralateral turns induced by L-DOPA. However, the coadministration of rimonabant and MSX-3, or SCH 58261, with L-DOPA did not significantly increase contralateral turning with respect to that produced by the A2AR antagonists. Moreover, neither rimonabant (1 mg/kg) alone nor the combined administration of rimonabant and MSX-3 significantly reduced tremulous jaw movements induced by tacrine. These results showed that CB1R blockade does not seem to influence positively the efficacy of A2AR antagonists in these models of PD.