title: The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine (IKE), Linköping University, SE-581 83, Linköping, Sweden.
authors: Abdul Maruf Asif
authors: AM
authors: Aziz
authors: University of Miami Health System, University of Miami, Miami, FL, USA.
authors: Shaun
authors: S
authors: Brothers
authors: University of Miami Health System, University of Miami, Miami, FL, USA.
authors: Gregory
authors: G
authors: Sartor
authors: Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine (IKE), Linköping University, SE-581 83, Linköping, Sweden.
authors: Lovisa
authors: L
authors: Holm
authors: Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine (IKE), Linköping University, SE-581 83, Linköping, Sweden.
authors: Markus
authors: M
authors: Heilig
authors: University of Miami Health System, University of Miami, Miami, FL, USA.
authors: Claes
authors: C
authors: Wahlestedt
authors: Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine (IKE), Linköping University, SE-581 83, Linköping, Sweden. annika.thorsell@liu.se.
authors: Annika
authors: A
authors: Thorsell
mesh_terms: D000437:Alcoholism; D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage*; D008024:Ligands; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D013375:Substance Withdrawal Syndrome; D000094942:Nociceptin Receptor
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D008024:Ligands; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C000722285:Oprl1 protein, rat
keywords: Agonist; Alcohol; Elevated plus-maze; Nociception/orphanin FQ; Operant; Reinstatement; Wistar rat