Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia.

Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2 Rs). Striatal D2 R functioning may be finely regulated by either adenosine A2A receptor (A2A R) or angiotensin receptor type 1 (AT1 R) through putative receptor heteromers. Here, we examined whether A2A R and AT1 R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1 R-A2A R interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1 R and A2A R bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1 R/A2A R heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1 R/A2A R complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1 R/A2A R oligomers with potential usefulness for the therapeutic management of TD.