Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 43; no. 9; pp. 1805 - 1812
• Main Authors: Domi, E, Barbier, E, Augier, E, Augier, G, Gehlert, D, Barchiesi, R, Thorsell, A, Holm, L, Heilig, M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2018; Springer International Publishing
• Subjects: Alcohol Deterrents - pharmacology; Alcohol use; Alcoholism - blood; Alcoholism - drug therapy; Alcohols; Animal models; Animals; Anxiety; Anxiety - drug therapy; Behavior; Benzamides - pharmacology; Central Nervous System Depressants - administration & dosage; Central Nervous System Depressants - chemistry; Corticosterone - blood; Dose-Response Relationship, Drug; Drinking behavior; Drug self-administration; Drug-Seeking Behavior - drug effects; Ethanol - administration & dosage; Male; Metabolism; Molecular chains; Narcotic Antagonists - pharmacology; Narcotics; Opioid receptors (type kappa); Prolactin - blood; Pyrrolidines - pharmacology; Rats, Wistar; Receptors, Opioid, kappa - antagonists & inhibitors; Self Administration; Stress; Substance Withdrawal Syndrome - blood; Substance Withdrawal Syndrome - drug therapy
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-018-0015-y

Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.