l-DOPA-treatment in primates disrupts the expression of A2A adenosine-CB1 cannabinoid-D2 dopamine receptor heteromers in the caudate nucleus

The molecular basis of priming for l-DOPA-induced dyskinesias in Parkinson's disease (PD), which depends on the indirect pathway of motor control, is not known. In rodents, the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A2A adenosine, CB1 cannabinoid and D2 dopamine receptors that regulate dopaminergic neurotransmission. The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson's disease and to determine whether their expression and pharmacological properties are altered upon l-DOPA treatment. By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint, we discovered a regional distribution of A2A/CB1/D2 receptor heteromers that predicts differential D2-mediated neurotransmission in the caudate-putamen of Macaca fascicularis. Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP-treated monkeys, l-DOPA treatment blunted the biochemical fingerprint and led to weak heteromer expression. These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A2A-CB1-D2 receptor heteromers may be successful to either normalize basal ganglia output or prevent L-DOPA-induced side effects.