It has recently been demonstrated that adenosine A2A receptors (A2AR) may interact at the striatal level with cannabinoid CB1 receptors (CB1R), leading to the formation of G protein-coupled receptor heteromers; these interactions have been suggested to participate in the antiparkinsonian effects of A2AR antagonists. To clarify this issue, we investigated the effects of a new drug combination interacting with A2AR and CB1R in rat models of Parkinson’s disease (PD). The CB1R antagonist rimonabant, and the adenosine A2AR antagonist MSX-3 were administered alone, in combination, or togehter with a sub-threshold dose of L-DOPA in two PD models: (1) contralateral turning behavior in rats bearing a unilateral lesion induced by the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA); (2) tremulous jaw movements induced in rats by the acethylcholinesterase inhibitor tacrine. In 6-OHDA-lesioned rats, administration of either rimonabant (1 mg/kg) or MSX-3 (3 mg/kg i.p.), or of their combination did not stimulate contralateral turning. Moreover, rimonabant (1 mg/kg) did not amplify L-DOPA-induced contralateral turning, whilst MSX-3 (3 mg/kg) significantly potentiated this effect of L-DOPA. However, the combined administration of rimonabant (1 mg/kg) and MSX-3 (3 mg/kg) did not further amplify L-DOPA-induced contralateral turning when compared to the administration of MSX-3 (3 mg/kg) alone. Finally, rimonabant (1 mg/kg) and MSX- 3 (3 mg/kg), administered either alone or in combination, did not significantly counteract tremulous jaw movements induced by tacrine. Taken together, these results suggest that the interaction with CB1R might not be a critical mechanism for the mediation of antiparkinsonian effects by A2AR antagonists.
Evaluation of drugs acting on CB1-A2A receptor oligomers in rat models of Parkinson's disease
COSTA G;
2012-01-01
Abstract
It has recently been demonstrated that adenosine A2A receptors (A2AR) may interact at the striatal level with cannabinoid CB1 receptors (CB1R), leading to the formation of G protein-coupled receptor heteromers; these interactions have been suggested to participate in the antiparkinsonian effects of A2AR antagonists. To clarify this issue, we investigated the effects of a new drug combination interacting with A2AR and CB1R in rat models of Parkinson’s disease (PD). The CB1R antagonist rimonabant, and the adenosine A2AR antagonist MSX-3 were administered alone, in combination, or togehter with a sub-threshold dose of L-DOPA in two PD models: (1) contralateral turning behavior in rats bearing a unilateral lesion induced by the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA); (2) tremulous jaw movements induced in rats by the acethylcholinesterase inhibitor tacrine. In 6-OHDA-lesioned rats, administration of either rimonabant (1 mg/kg) or MSX-3 (3 mg/kg i.p.), or of their combination did not stimulate contralateral turning. Moreover, rimonabant (1 mg/kg) did not amplify L-DOPA-induced contralateral turning, whilst MSX-3 (3 mg/kg) significantly potentiated this effect of L-DOPA. However, the combined administration of rimonabant (1 mg/kg) and MSX-3 (3 mg/kg) did not further amplify L-DOPA-induced contralateral turning when compared to the administration of MSX-3 (3 mg/kg) alone. Finally, rimonabant (1 mg/kg) and MSX- 3 (3 mg/kg), administered either alone or in combination, did not significantly counteract tremulous jaw movements induced by tacrine. Taken together, these results suggest that the interaction with CB1R might not be a critical mechanism for the mediation of antiparkinsonian effects by A2AR antagonists.
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