Oliveira, Paulo A.Dalton, James A. R.López-Cano, MarcRicarte, AdriàMorató Arús, XavierMatheus, Filipe C.Cunha, Andréia S.Müller, Christa E.Takahashi, Reinaldo N.Fernández Dueñas, VíctorGiraldo, JesúsPrediger, Rui D.Ciruela Alférez, Francisco2018-04-302018-04-302017-05-122045-2322https://hdl.handle.net/2445/121970Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR 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 AT1R/A2AR 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 AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.12 p.application/pdfengcc-by (c) Oliveira, Paulo A. et al., 2017http://creativecommons.org/licenses/by/3.0/esTrastorns motorsAdenosinaDopaminaAntipsicòticsNeurotransmissorsMovement disordersAdenosineDopamineAntipsychotic drugsNeurotransmittersinfo:eu-repo/semantics/article6794372018-04-30info:eu-repo/semantics/openAccess28500295