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

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