Compound May Curb Alcohol Dependence

Summary: The compound LY2444296, which blocks the kappa opioid receptor, significantly reduces alcohol consumption in animal models of alcohol dependence. This study suggests LY2444296 could be a breakthrough in treating alcohol use disorder (AUD) by targeting the brain’s KOP system, implicated in addiction and withdrawal symptoms.

Unlike previous compounds, LY2444296 showed promise in reducing withdrawal signs and alcohol intake after short-term abstinence, without affecting non-dependent individuals. The findings pave the way for further exploration into how this compound and similar ones might offer new treatment avenues for AUD, emphasizing the need to understand the specific brain regions involved in withdrawal and relapse.

Key Facts:

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

Source: Scripps Research Institute

Scripps Research scientists have found that LY2444296—a compound that selectively blocks the kappa opioid receptor (KOP)—may reduce drinking in cases of alcohol dependence in animal studies.

The findings, which were published March 9, 2024, in Scientific Reports, could eventually inform new treatment options for people who experience alcohol use disorder (AUD).

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

This shows a glass of scotch.
Next on their agenda, Martin-Fardon and Flores-Ramirez hope to determine whether LY24444296 can block the effects of stress and other cues that can trigger alcohol relapse. Credit: Neuroscience News

“The KOP system is also important in alcohol use disorder, so the idea is if it’s 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. Both acute and chronic exposure to alcohol negatively affects this system, according to the study’s first author, Francisco Flores-Ramirez, PhD, a postdoctoral fellow at Scripps Research.

For their study, Martin-Fardon and Flores-Ramirez sought to find out whether orally administering LY2444296 could decrease alcohol consumption in rats that formed alcohol dependency. The aim was to mitigate withdrawal symptoms, which would hypothetically lead to reduced alcohol intake.

Once rats received LY2444296 at doses as low as 3 mg per kg following 8 hours of abstinence—when acute withdrawal symptoms typically start— withdrawal signs and alcohol consumption tapered down significantly. The researchers also determined that LY2444296 may be innocuous, as it had neither a positive nor negative effect on rats without alcohol dependency.

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

“People drink to get rid of the sensations of withdrawal,” Martin-Fardon says. He added that withdrawal is associated with physical pain, and that oftentimes, “the only thing that can fix the problem is to have a drink.” But if LY2444296 is taken before withdrawal symptoms begin, “you can decrease the symptoms, so you feel better and drink less.”

Still, the question remains which specific parts of the brain are best targeted to mitigate withdrawal symptoms. Next on their agenda, Martin-Fardon and Flores-Ramirez hope to determine whether LY24444296 can block the effects of stress and other cues that can trigger alcohol relapse.

“We’re also interested in what brain regions are changing as a function of alcohol dependence,” Flores-Ramirez says. “Maybe we could target them to see if the compound could reverse both drinking and relapse behavior.”

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 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


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) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states.

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

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

After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) 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 LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence.

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

These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD.

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