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Mol Neurobiol. 2018 Jun;55(6):4952-4958. doi: 10.1007/s12035-017-0696-y. Epub 2017 Aug 5.

Antipsychotic-Like Efficacy of Dopamine D2 Receptor-Biased Ligands is Dependent on Adenosine A2A Receptor Expression.

Author information

1
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
2
Department of Neuroscience, Karolinska Institute, Solna, Stockholm, Sweden.
3
Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
4
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. fciruela@ub.edu.
5
Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain. fciruela@ub.edu.
6
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. vfernandez@ub.edu.
7
Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain. vfernandez@ub.edu.

Abstract

Dopamine D2 receptor (D2R) activation triggers both G protein- and β-arrestin-dependent signaling. Biased D2R ligands activating β-arrestin pathway have been proposed as potential antipsychotics. The ability of D2R to heteromerize with adenosine A2A receptor (A2AR) has been associated to D2R agonist-induced β-arrestin recruitment. Accordingly, here we aimed to demonstrate the A2AR dependence of D2R/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 D2R/A2AR homomers and heteromers, we demonstrated that the D2R agonists quinpirole and UNC9994 could promote β-arrestin-2 recruitment only when A2AR/D2R heteromers were expressed. Subsequently, the role of A2AR in the antipsychotic-like activity of UNC9994 was assessed in wild-type and A2AR-/- mice administered with phencyclidine (PCP) or amphetamine (AMPH). Interestingly, while UNC9994 reduced hyperlocomotion in wild-type animals treated either with PCP or AMPH, in A2AR-/- 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 D2R/A2AR heteromerization facilitates D2R β-arrestin recruitment, and furthermore, reveal a pivotal role for A2AR in the antipsychotic-like activity of the β-arrestin-biased D2R ligand, UNC9994.

KEYWORDS:

Adenosine A2A receptor; BRET; Functional selectivity, biased ligand, dopamine D2 receptor; Oligomerization; β-arrestin

PMID:
28779351
DOI:
10.1007/s12035-017-0696-y
[Indexed for MEDLINE]

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