The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models.

Abdul Maruf Asif Aziz,Annika Thorsell,Claes Wahlestedt,Lovisa Holm,Markus Heilig,Gregory Sartor,Shaun Brothers

doi:10.1007/s00213-016-4385-8

Abdul Maruf Asif Aziz, Annika Thorsell + Show 5 more

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https://doi.org/10.1007/s00213-016-4385-8

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Journal: Psychopharmacology	Publication Date: Aug 11, 2016
Citations: 26	License type: CC BY 4.0

Affiliation: Linköping University, University of Miami

Abstract

RationaleAlcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.ObjectivesHere, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.ResultsSR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced (“hangover”) anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.ConclusionThese findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

Highlights

Nociceptin/orphanin FQ (N/OFQ), a heptadecapeptide, was discovered as an endogenous ligand for the orphan Gprotein-coupled receptor opioid receptor like-1 (ORL1), or the nociceptin/orphanin FQ (NOP; (Meunier 1997; Meunier et al 1995; Reinscheid et al 1995)) receptor
SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced
Evidence suggests that the N/OFQ–NOP system is a promising target for pharmacotherapy aimed at reducing excessive alcohol consumption and preventing relapse

Summary

Introduction

Nociceptin/orphanin FQ (N/OFQ), a heptadecapeptide, was discovered as an endogenous ligand for the orphan Gprotein-coupled receptor opioid receptor like-1 (ORL1), or the nociceptin/orphanin FQ (NOP; (Meunier 1997; Meunier et al 1995; Reinscheid et al 1995)) receptor. An impairment of NOP-receptor G-protein coupling is present in central amygdala (CeA) of mSP rats and can be overcome by intracerebroventricular or CeA injections of N/OFQ to rescue the excessive alcohol consumption of this line (Ciccocioppo et al 2003; Economidou et al 2008). Wistar rats without a history of dependence are not sensitive to suppression of alcohol self-administration or stress responses by N/OFQ. A history of dependence results in escalation of alcohol self-administration, sensitized stress responses, and increased expression of NOP. Under these conditions, administration of N/OFQ reduces alcohol intake and produces anxiolytic-like effects (Martin-Fardon et al 2010). Central administration of N/OFQ suppresses relapse-like behavior induced by both these classes of stimuli (Ciccocioppo et al 2004; Martin-Fardon et al 2000)

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