L-DOPA disrupts adenosine A2A-cannabinoid CB1-dopamine D2 receptor heteromer cross-talk in the striatum of hemiparkinsonian rats: Biochemical and behavioral studies

Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A(2A) receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A(2A), cannabinoid CB1 and dopamine D-2 receptors may interact and form functional A(2A)-CB1-D-2 receptor heteromers in co-transfected cells as well as in rat striatum. These data suggest that treatment with a combination of drugs or a single compound selectively acting on A(2A)-CB1-D-2 heteromers may represent an alternative therapeutic treatment of PD. We investigated the expression of A(2A)-CB1-D-2 receptor heteromers in the striatum of both naIve and hemiparkinsonian rats (HPD-rats) bearing a unilateral 6-hydroxydopamine (6-0HDA) lesion, and assessed how receptor heteromer expression and biochemical properties were affected by L-DOPA treatment. Radioligand binding data showed that A(2A)-CB1-D-2 receptor heteromers are present in the striatum of both na ve and HPD-rats. However, behavioral results indicated that the combined administration of A(2A) (MSX-3 or SCH58261) and CB1 (rimonabant) receptor antagonists, in the presence of L-DOPA does not produce a response different from administration of the A(2A) receptor antagonist alone. These behavioral results prompted identification of heteromers in L-DOPA-treated animals. Interestingly, the radioligand binding results in samples from lesioned animals suggest that the heteromer is lost following acute or chronic treatment with L-DOPA. (C) 2014 Elsevier Inc. All rights reserved.