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

Dopamine D ₂ receptor (D ₂ R) activation triggers both G protein- and β-arrestin-dependent signaling. Biased D ₂ R ligands activating β-arrestin pathway have been proposed as potential antipsychotics. The ability of D ₂ R to heteromerize with adenosine A _2A receptor (A _2A R) has been associated to D ₂ R agonist-induced β-arrestin recruitment. Accordingly, here we aimed to demonstrate the A _2A R dependence of D ₂ 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 D ₂ R/A _2A R homomers and heteromers, we demonstrated that the D ₂ R agonists quinpirole and UNC9994 could promote β-arrestin-2 recruitment only when A _2A R/D ₂ R heteromers were expressed. Subsequently, the role of A _2A R in the antipsychotic-like activity of UNC9994 was assessed in wild-type and A _2A 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 A _2A 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 D ₂ R/A _2A R heteromerization facilitates D ₂ R β-arrestin recruitment, and furthermore, reveal a pivotal role for A _2A R in the antipsychotic-like activity of the β-arrestin-biased D ₂ R ligand, UNC9994.