Compound May Curb Alcohol Dependence

Summary: The compound LY2444296, which blocks the kappa opioid receptor, significantly reduced alcohol consumption in animal models of alcohol dependence. This study suggests that LY2444296 could provide a major breakthrough in the treatment of alcohol use disorders (AUD) by targeting the brain’s KOP system, which is involved in addiction and withdrawal symptoms.

Unlike previous compounds, LY2444296 showed promise in reducing withdrawal signs and alcohol consumption after short-term abstinence, without affecting non-dependent individuals. The findings pave the way for further exploration of how this compound and others like it could offer new treatment avenues for AUD, highlighting the need to understand specific brain regions involved in withdrawal and relapse .

Highlights:

1. LY2444296 targets the kappa opioid receptor, demonstrating the potential to reduce alcohol consumption in alcohol-dependent rats without affecting non-dependent rats.
2. The compound successfully reduced withdrawal symptoms and alcohol consumption after just 8 hours of abstinence, a critical period for the onset of withdrawal.
3. Funded by the National Institute on Alcohol Abuse and Alcoholism, the research marks an important step toward identifying new treatments for alcohol use disorders, focusing on the brain circuits underlying -currents affected by dependence and withdrawal.

Source: Scripps Research Institute

Scripps Research scientists have found that LY2444296, a compound that selectively blocks the kappa opioid receptor (KOP), can reduce alcohol consumption in alcohol dependence in animal studies.

The results, published on March 9, 2024 in Scientific reportscould potentially inform new treatment options for people with alcohol use disorder (AUD).

“Compounds designed to selectively block KOP are very promising because this receptor is implicated in many mental illnesses, such as anxiety and depression,” explains Rémi Martin-Fardon, PhD, associate professor in the Department of Molecular Medicine.

“The KOP system is also important in alcohol use disorders, so the idea is that if it is targeted and blocked, you can stop alcohol abuse.”

The KOP system controls brain circuits that affect a range of neurological processes, including addiction, emotion, pain, and reward seeking. Acute and chronic exposure to alcohol negatively affects this system, according to the study’s first author, Francisco Flores-Ramirez, PhD, a postdoctoral researcher at Scripps Research.

For their study, Martin-Fardon and Flores-Ramirez investigated whether oral administration of LY2444296 could decrease alcohol consumption in rats that had developed alcohol dependence. The goal was to alleviate withdrawal symptoms, which would hypothetically lead to a reduction in alcohol consumption.

Once rats were given LY2444296 at doses as low as 3 mg per kg after 8 hours of abstinence – when acute withdrawal symptoms typically begin – withdrawal signs and alcohol consumption decreased significantly. The researchers also determined that LY2444296 might be harmless because it had neither positive nor negative effects on rats without alcohol dependence.

Martin-Fardon and his team did not expect LY2444296 to reduce signs of withdrawal after just 8 hours of alcohol abstinence, because previous studies had shown that other compounds capable of binding to KOP had no effect. no effect on alcohol withdrawal. The scientists don’t yet know why LY2444296 was effective in the current study, and they plan to investigate further.

“People drink to get rid of withdrawal feelings,” says Martin-Fardon. He added that withdrawal is associated with physical pain and that often “the only thing that can solve the problem is having a drink.” But if LY2444296 is taken before withdrawal symptoms appear, “you may reduce the symptoms, so you will feel better and drink less.”

It remains to be seen which specific parts of the brain are best targeted to alleviate withdrawal symptoms. Next, Martin-Fardon and Flores-Ramirez hope to determine whether LY24444296 can block the effects of stress and other signals that can trigger alcohol relapse.

“We are also interested in which regions of the brain change with alcohol dependence,” says Flores-Ramirez. “Perhaps we could target them to see if the compound could reverse both drinking behaviors and relapse.”

Funding: This work and the researchers involved were supported by funding from the National Institute on Alcohol Abuse and Alcoholism (grants AA028549, AA026999, AA006420, and T32 AA007456).

About this research news in neuropharmacology and alcohol use disorders

Author: Melissa Suran
Source: Scripps Research Institute
Contact: Melissa Suran – Scripps Research Institute
Picture: Image is credited to Neuroscience News

Original research: Free access.
“LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol consumption 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 consumption in male and female Wistar rats with a history of alcohol dependence

Alcohol use disorders (AUDs) remain a major public health problem. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in the actions of alcohol, particularly in its negative affective states associated with withdrawal.

This study tested the ability of LY2444296, a short-acting selective KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats after 8 hours of abstinence.

Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent exposure to alcohol vapor for 6 weeks or exposed to air (independent).

After 6 weeks, the effect of LY2444296 (0, 3 and 10 mg/kg, po) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel and their somatic withdrawal signs and alcohol self-administration were measured after administration of LY2444296 at 8 h, 2 weeks and 4 weeks of abstinence.

LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats after 8 hours of abstinence only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats after only 8 hours of abstinence.

These findings highlight the DYN/KOP system in alcohol actions during acute abstinence, suggesting that KOP antagonism may be beneficial in attenuating acute withdrawal signs and, therefore, significantly reducing excessive drinking. of alcohol associated with AUD.