Aticaprant (Clinically Developed Kappa-Opioid Receptor Antagonist) Combined With Naltrexone Prevents Alcohol “Relapse” Drinking
Year: 2020
Type: article
Abstract: Inviting Innovationsof alcohol access when alcohol is available again [21].Our particularly relevant question was whether there was an upregulated KOR activity after prolonged withdrawal or abstinence and during alcohol relapselike drinking, and if so, whether blockade of KOR could reduce the ADE or not.To date, however, there is no study investigating effects of the novel KOR antagonist aticaprant on alcohol "relapse" in rodent ADE models.Aticaprant (LY-2456302, CERC-501 or JNJ-67953964) is a selective and short-acting KOR antagonist and has recently been under development for the potential treatment of major depressive disorder [11,22,23].Based on recent studies showing that aticaprant attenuates alcohol self-administration, reduces alcohol intake escalation, and prevents stress-induced seeking in rodents [11,12], we proposed a new hypothesis that aticaprant could prevent alcohol relapse-like drinking in ADE model.As alcohol relapse is an important target for medications development for alcoholism, we specifically investigated the pharmacological effects of aticaprant on mouse ADE in both sexes, to ascertain its potential as an antirelapse compound.As nor-binaltorphimine (nor-BNI) is a selective, but long-acting, KOR antagonist, we purposely used nor-BNI as a reference compound and compared its effect with aticaprant.Alcohol increases mu-opioid receptor (MOR)-mediated signal which is responsible for alcohol's positive reinforcing and motivational properties and is highly involved in alcohol relapse episodes.MOR antagonist naltrexone decreases alcohol craving and relapse in humans [24], and relapse-like drinking in rodent ADE models [1,18].Among multiple actions of alcohol in the CNS, both KOR and MOR activities are profoundly changed by alcohol exposure in humans [25,26], We further hypothesized that by targeting on both KOR and MOR, the combination of the clinically developed aticaprant and naltrexone would improve efficacy over the single-receptor approach on preventing relapse [18].Therefore, the present study examined whether the appropriate combination of aticaprant and naltrexone could be more effective in preventing ADE than each alone. Materials & Methods AnimalsBoth male and female C57BL/6J mice (8-week-old) were
Author: Y Zhou
Institution: Rockefeller University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4230134602