Antipsychotic-Like Efficacy of Dopamine D 2 Receptor-Biased Ligands is Dependent on Adenosine A 2A Receptor Expression.

Dopamine D2 receptor (D2 R) activation triggers both G protein- and β-arrestin-dependent signaling. Biased D2 R ligands activating β-arrestin pathway have been proposed as potential antipsychotics. The ability of D2 R to heteromerize with adenosine A2A receptor (A2A R) has been associated to D2 R agonist-induced β-arrestin recruitment. Accordingly, here we aimed to demonstrate the A2A R dependence of D2 R/β-arrestin signaling. By combining bioluminescence resonance energy transfer (BRET) between β-arrestin-2 tagged with yellow fluorescent protein and bimolecular luminescence complementation (BiLC) of D2 R/A2A R homomers and heteromers, we demonstrated that the D2 R agonists quinpirole and UNC9994 could promote β-arrestin-2 recruitment only when A2A R/D2 R heteromers were expressed. Subsequently, the role of A2A R in the antipsychotic-like activity of UNC9994 was assessed in wild-type and A2A R-/- mice administered with phencyclidine (PCP) or amphetamine (AMPH). Interestingly, while UNC9994 reduced hyperlocomotion in wild-type animals treated either with PCP or AMPH, in A2A R-/- mice, it failed to reduce PCP-induced hyperlocomotion or produced only a moderate reduction of AMPH-mediated hyperlocomotion. Overall, the results presented here reinforce the notion that D2 R/A2A R heteromerization facilitates D2 R β-arrestin recruitment, and furthermore, reveal a pivotal role for A2A R in the antipsychotic-like activity of the β-arrestin-biased D2 R ligand, UNC9994.