β-Arrestin 2 dependence of δ  opioid receptor agonists is  correlated with alcohol intake.
OBJECTIVE
δ 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 δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β-arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists.


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


RESULTS
All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β-arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β-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 β-arrestin 2-dependent.


CONCLUSIONS
Our finding that δ receptor agonists that strongly recruit β-arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
T
T
Chiang
K
K
Sansuk
R M
RM
van Rijn
D000428:Alcohol Drinking / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide