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

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

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Abstract: Rationale: Alcoholism 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. Objectives: Here, 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. Results: SR-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. Conclusion: These 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.

Original languageEnglish (US)
Pages (from-to)3553-3563
Number of pages11
JournalPsychopharmacology
Volume233
Issue number19-20
DOIs
StatePublished - Oct 1 2016

Keywords

  • Agonist
  • Alcohol
  • Elevated plus-maze
  • Nociception/orphanin FQ
  • Operant
  • Reinstatement
  • Wistar rat

ASJC Scopus subject areas

  • Pharmacology

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