?-Arrestin 2 dependence of ? opioid receptor agonists is correlated with alcohol intake.

ABSTRACT:

Background and purpose

? Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that ? receptor agonists range widely in their ability to modulate alcohol intake; certain ? receptor agonists actually increase alcohol consumption in mice. We propose that variations in ?-arrestin 2 recruitment contribute to the differential behavioural profile of ? receptor agonists.

Experimental approach

We used three diarylmethylpiperazine-based non-peptidic ? receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse ? receptor agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and ?-arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used ?-arrestin 2 knockout mice and a model of depression-like behaviour to further study the role of ?-arrestin 2 in ? receptor pharmacology.

Key results

All six tested ? receptor agonists were full agonists in the cAMP assay but displayed distinct ?-arrestin 2 recruitment efficacy. The efficacy of ? receptor agonists to recruit ?-arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behaviour were ?-arrestin 2-dependent.

Conclusions and implications

Our finding that ? receptor agonists that strongly recruit ?-arrestin 2 can increase alcohol intake carries important ramifications for drug development of ? receptor agonists for treatment of alcohol use disorders and depressive disorders.

SUBMITTER: Chiang T 

PROVIDER: S-EPMC4940619 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature