Evaluation of drugs acting on D2-CB1-A2A receptor oligomers in rat models of Parkinson's disease

Adenosine A2A receptors (A2AR) represent a new target for drug development in Parkinson's Disease (PD). Preclinical data and clinical trials suggest that A2AR antagonists can provide symptomatic improvement by potentiating the effect of L-DOPA without worsening dyskinesia. 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 reports demonstrated that A2AR, CB1R and D2R 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 a 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 model of PD: 1) contralateral turning behavior in rats bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigrostriatal pathway; 2) parkinsonian tremulous jaw movements induced by tacrine. 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 both A2AR antagonists, MSX-3 (3 mg/kg) and 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 significant increase contralateral turning with respect to that produced by the A2AR antagonists. Moreover, either rimonabant (1 mg/ kg) alone or the combined administration of rimonabant and MSX-3 did not significantly reduce 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.