Summary: The selective kappa opioid receptor (KOP) antagonist LY2444296 markedly reduced alcohol consumption and eased withdrawal signs in animal models of alcohol dependence. These preclinical findings point to LY2444296 as a promising candidate for treating alcohol use disorder (AUD) by targeting the brain’s dynorphin/KOP system, which contributes to addiction-related negative emotional states and withdrawal-driven drinking.
In contrast to earlier KOP-targeting compounds, LY2444296 decreased withdrawal symptoms and lowered alcohol intake after a short abstinence period, while producing no measurable effects in non-dependent animals. The results encourage further investigation into how LY2444296 and related agents could be developed into treatments for AUD, and highlight the importance of identifying the specific brain circuits and stress- or cue-related triggers involved in withdrawal and relapse.
Key Facts:
- LY2444296 selectively blocks the kappa opioid receptor and lowered alcohol consumption in rats with a history of dependence, without affecting alcohol intake in non-dependent control rats.
- The compound reduced both physical signs of withdrawal and alcohol self-administration when administered after just 8 hours of abstinence—a critical window when acute withdrawal typically begins.
- Supported by the National Institute on Alcohol Abuse and Alcoholism, this research advances the search for new AUD treatments by focusing on the dynorphin/KOP system and the neural circuits that drive withdrawal and compulsive drinking.
Source: Scripps Research Institute
Scripps Research scientists report that LY2444296, a selective antagonist of the kappa opioid receptor (KOP), can reduce alcohol intake in animal models of dependence.
Published March 9, 2024 in Scientific Reports, the study sheds light on how KOP antagonism may blunt the negative states that drive excessive drinking in alcohol use disorder (AUD).
“KOP-selective compounds show strong potential because this receptor contributes to a variety of psychiatric conditions, including anxiety and depression,” explains Rémi Martin-Fardon, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.
The dynorphin (DYN)/KOP system regulates neural circuits involved in emotion, pain, reward, and addictive behavior. Both short- and long-term alcohol exposure alter this system, potentially contributing to the negative affect and heightened motivation to drink that characterize withdrawal, according to first author Francisco Flores-Ramirez, PhD, a postdoctoral fellow at Scripps Research.
In the study, Martin-Fardon and Flores-Ramirez examined whether oral doses of LY2444296 could reduce alcohol self-administration in Wistar rats that had been rendered dependent through repeated alcohol exposure. The working hypothesis was that reducing withdrawal severity would in turn lower alcohol-seeking and consumption.
Rats were trained to self-administer 10% alcohol for 30 minutes daily across 21 sessions and then made dependent via six weeks of chronic intermittent alcohol vapor exposure; control animals were exposed to air. When LY2444296 was given orally at doses as low as 3 mg/kg after 8 hours of abstinence—the period when acute withdrawal signs typically emerge—dependent rats showed significantly reduced physical withdrawal signs and a pronounced decrease in alcohol intake. Importantly, the compound had no clear positive or negative behavioral effects in non-dependent rats, suggesting a degree of selectivity for dependence-related pathology.
The investigators were surprised that LY2444296 produced measurable benefits after only 8 hours of abstinence, because prior KOP-targeting compounds had not shown this early effectiveness against withdrawal. The reason for LY2444296’s rapid impact is not yet understood, and the team plans further studies to clarify the mechanism and time course of its action.
“Many people drink to relieve the distressing sensations of withdrawal,” Martin-Fardon says. “Withdrawal often involves physical discomfort and negative mood states, which drive relapse. If a KOP antagonist like LY2444296 is given before withdrawal intensifies, it may lessen those symptoms, reduce the urge to drink, and help people maintain abstinence.”
The researchers emphasize that identifying which brain regions and circuits are most affected by alcohol dependence will be crucial for understanding where LY2444296 acts to reduce withdrawal and relapse-like behaviors. Martin-Fardon and Flores-Ramirez intend to test whether LY2444296 can block stress-induced or cue-driven relapse and to map regional brain changes associated with dependence and compound treatment.
Funding: This research and the investigators were supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA028549, AA026999, AA006420, and T32 AA007456).
About this neuropharmacology and alcohol use disorder research news
Author: Melissa Suran
Source: Scripps Research Institute
Contact: Melissa Suran – Scripps Research Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence” by Rémi Martin-Fardon et al. Scientific Reports
Abstract
LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence
Alcohol use disorder (AUD) is a persistent public health challenge. The dynorphin (DYN)/κ-opioid receptor (KOP) system contributes to alcohol’s effects, especially the negative affective states that accompany withdrawal. This study evaluated LY2444296, a selective, short-acting KOP antagonist, for its ability to reduce alcohol self-administration in dependent male and female Wistar rats at 8 hours of abstinence.
Rats were trained to orally self-administer 10% alcohol (30 minutes per day for 21 sessions) and then were exposed to chronic intermittent alcohol vapor for six weeks to induce dependence; control animals were exposed to air. After six weeks, LY2444296 (0, 3, and 10 mg/kg, orally) was tested for effects on alcohol self-administration at 8 hours abstinence. A separate cohort was evaluated for somatic withdrawal signs and drinking after LY2444296 administration at 8 hours, 2 weeks, and 4 weeks of abstinence.
LY2444296 at both 3 and 10 mg/kg significantly reduced physical withdrawal signs in dependent rats at the 8-hour abstinence time point only. Correspondingly, these doses selectively decreased alcohol self-administration in dependent animals at 8 hours abstinence. These findings underscore the role of the DYN/KOP system during acute abstinence and suggest that KOP antagonism may be an effective strategy to alleviate acute withdrawal symptoms and, consequently, reduce excessive alcohol consumption associated with AUD.