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

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.

• Authors: Abdul Maruf Asif Aziz, Shaun Brothers, Gregory Sartor, Lovisa Holm, Markus Heilig, Claes Wahlestedt, Annika Thorsell
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 233 Issue 19-20 Pg. 3553-63 (Oct 2016) ISSN: 1432-2072 [Electronic] Germany
• PMID: 27515665 (Publication Type: Journal Article)

Chemical References

• Central Nervous System Depressants
• Ligands
• Receptors, Opioid
• Ethanol
• Nociceptin Receptor
• Oprl protein, rat

Topics

• Alcoholism
• Animals
• Anxiety
• Behavior, Animal (drug effects)
• Central Nervous System Depressants (administration & dosage)
• Conditioning, Operant (drug effects)
• Drug-Seeking Behavior (drug effects)
• Ethanol (administration & dosage)
• Ligands
• Male
• Rats
• Rats, Wistar
• Receptors, Opioid (agonists)
• Reinforcement, Psychology
• Reward
• Self Administration
• Substance Withdrawal Syndrome
• Nociceptin Receptor