Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands. (June 2016)

• Record Type: Journal Article
• Authors: Asth, L.; Ruzza, C.; Malfacini, D.; Medeiros, I.; Guerrini, R.; Zaveri, N.T.; Gavioli, E.C.; Calo', G.
• Is Part Of: Neuropharmacology. Volume 105(2016)
• Page Start: 434
• Page End: 442
• Publication Date: 2016-06
• Subjects: N/OFQ -- Anxiety -- Depression -- G protein -- β-arrestin -- NOP receptor partial agonist -- BRET -- Elevated plus maze -- Forced swim test -- Mouse; N/OFQ nociceptin/orphanin FQ -- NOP N/OFQ peptide receptor -- GPCR G protein-coupled receptor -- HEK293 Human Embryonic Kidney -- EPM elevated plus maze -- FST forced swim test -- BRET bioluminescence resonance energy transfer; N/OFQ (PubChem CID: 16131448) -- UFP-101 (PubChem CID: 25081457) -- SB-612111 (PubChem CID: 10047612); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.02.003
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Background and purpose: Nociceptin/orphanin FQ (N/OFQ) receptor (NOP) agonists produce anxiolytic-like effects in rodents while antagonists promote antidepressant-like effects. The aim of this study was to investigate the effect on anxiety and depression of NOP receptor partial agonists such as the peptides [F/G]N/OFQ(1-13)NH2 and UFP-113 and the non-peptide AT-090. Experimental approach: In vitro AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 were tested for their ability to promote NOP/G-protein and NOP/β-arrestin 2 interaction, using a bioluminescence resonance energy transfer assay. In vivo, they were tested in mice in the elevated plus maze (EPM) and in the forced swim (FST) tests. NOP partial agonists effects were systematically compared to those of full agonists (N/OFQ and Ro 65-6570) and antagonists (UFP-101 and SB-612111). Key results: In vitro, AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 promoted NOP/G protein interaction, with maximal effects lower than those evoked by N/OFQ and Ro 65-6570. AT-090 behaved as a NOP partial agonist also in inducing β-arrestin 2 recruitment, while UFP-113 and [F/G]N/OFQ(1-13)NH2 were inactive in this assay. In vivo, AT-090 induced anxiolytic-like effects in the EPM but was inactive in the FST. Opposite results were obtained with UFP-113 and [F/G]N/OFQ(1-13)NH2 . Conclusions and implications: NOP ligands producing similar effects on NOP/G protein interaction (partial agonism) but showing different effects on β-arrestin 2 recruitment (partial agonism vs antagonism) elicited different actions on anxiety and mood. These results suggest that the action of a NOP ligand on emotional states is better predicted based on its β-arrestin 2 rather than G-protein efficacy. Graphical abstract: Highlights: NOP agonists promote anxiolytic while antagonists antidepressant effects. AT-090, UFP-113 and [F/G] behaved as partial agonist at NOP/G protein. AT-090 was a partial agonist while UFP-113 and [F/G] antagonists at NOP/arrestin. In vivo AT-090 was anxiolytic while UFP-113 and [F/G] antidepressant. NOP ligands effects on emotional states depend on arrestin rather than G protein efficacy.