Summary: The kappa opioid receptor blocking compound LY2444296 significantly reduces alcohol-dependent alcohol consumption in animals. This study suggests that LY2444296 may be a breakthrough in the treatment of alcohol use disorder (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 symptoms and alcohol after short-term abstinence without affecting non-dependent individuals. The findings pave the way for further research into how these compounds and similar compounds may provide new therapeutic avenues for AUD, emphasizing the importance of understanding the specific brain regions involved in withdrawal and recovery.
Key facts:
- LY2444296 targets the kappa opioid receptor and shows potential to reduce alcohol consumption in alcohol-dependent mice without affecting non-dependent mice.
- The compound effectively reduced withdrawal symptoms and alcohol consumption after 8 hours of abstinence, the critical period for withdrawal.
- The research, funded by the National Institute on Alcohol Abuse and Alcoholism, is a major step toward identifying new treatments for alcohol use disorders by focusing on the brain circuits affected by addiction and alcoholism.
Source: Scripps Research Institute
Scripps Research scientists found that LY2444296—a compound that blocks the kappa opioid receptor (KOP)—can reduce drinking in alcohol dependence in animal studies.
In the year Published on March 9, 2024 Scientific reportsUltimately, it may inform new treatment options for people with alcohol use disorder (AUD).
“Compounds designed to selectively block KOP are very promising because this receptor is involved in many mental disorders such as anxiety and depression,” said Rémi Martin-Fardon, Ph.D., associate professor in the Department of Molecular Medicine.
“The cop system is also important in alcohol use disorders, so if the impulse is targeted and blocked, you can stop abusing alcohol.”
The KOP system controls brain circuits that affect a variety of neural processes, including addiction, mood, pain, and reward seeking. According to the study’s first author, Francisco Flores-Ramirez, PhD, a postdoctoral fellow at Scripps Research, both acute and chronic alcohol exposure negatively affect this system.
For their study, Martin-Fardon et Flores-Ramirez He sought to determine whether oral administration of LY2444296 could reduce alcohol consumption in alcohol-dependent rats. The aim was to reduce withdrawal symptoms, resulting in a reduction in alcohol consumption.
If rats received low doses of LY2444296 per kilogram after 8 hours of abstinence—when acute withdrawal symptoms usually begin—withdrawal symptoms and alcohol consumption were significantly reduced. The researchers also determined that LY2444296 may be harmless, as it had neither positive nor negative effects on mice without alcohol dependence.
Martin-Fardon and his team did not expect LY2444296 to reduce withdrawal symptoms after 8 hours of alcohol abstinence, as previous studies had shown that other compounds that can be combined with KOP had no effect on alcohol withdrawal. The scientists do not yet know why LY2444296 was effective in this study and plan to investigate further.
“People drink to avoid feelings of isolation,” says Martin-Fardon. He added that withdrawal is associated with physical pain, and often “the only thing that can fix the problem is drinking.” But if LY2444296 is taken before withdrawal symptoms start, “you can reduce the symptoms, so you feel better and drink less.”
Still, the question remains as to which specific parts of the brain are best at reducing healing symptoms. Next on their agenda, Martin-Fardón and Flores-Ramirez hope to determine whether LY24444296 can block anxiety and other symptoms that may lead to alcohol relapse.
“We’re also interested in what regions of the brain change as a result of alcohol dependence,” Flores-Ramirez said. “Maybe we can target them to see if the compound can reverse drinking and relapse behavior.”
Financial support This work and the participating researchers were supported by funding from the National Institute on Alcohol Abuse and Alcoholism (grants AA028549, AA026999, AA006420, and T32 AA007456).
So Neuropharmacology and Alcohol Use Disorders Research News
Author: Melissa Suran
Source: Scripps Research Institute
Contact: Melissa Suran – Scripps Research Institute
Image: Image credited to Neuroscience News.
Preliminary study: Open Access.
“LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol intake in male and female Wistar rats with a history of alcohol dependence.” by Remy Martin-Fardon et al. Scientific reports
Draft
LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol consumption 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 the actions of alcohol, particularly the negative affective states associated with withdrawal.
This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to induce alcohol self-administration during 8-hour abstinence in dependent male and female Wistar rats.
Animals were trained to self-administer 10% alcohol (30 min/day for 21 sessions) and exposed (neutralized) to chronic alcohol vapor exposure for 6 weeks.
After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, po) on alcohol self-administration was tested on 8-hour abstinence. A separate cohort of rats was prepared in parallel, and their somatic symptoms and alcohol self-administration were measured following LY2444296 administration at 8 hours, 2 weeks, and 4 weeks of abstinence.
LY2444296 at 3 and 10 mg/kg significantly reduced physical symptoms of withdrawal during 8 h abstinence in dependent rats. In addition, 3 and 10 mg/kg alcohol self-administration in dependent rats was reduced only after 8 hours of abstinence.
These results highlight the actions of the DYN/KOP system during acute abstinence, suggesting that KOP antagonism may be useful in reducing acute withdrawal symptoms, and in turn significantly reduce AUD-related binge drinking.