January 10, 2023

Scripps Research study suggests insomnia drug could be repurposed for alcohol use disorder Orexin-receptor antagonist suvorexant (Belsomra ) reduced alcohol intake and blocked relapse in preclinical tests.

January 10, 2023

LA JOLLA, CA An insomnia drug has shown promise as a potential treatment for alcohol use disorder, in a preclinical study from Scripps Research.

The drug, suvorexant (Belsomra ), blocks the activity of brain-cell receptors called orexin receptors, which normally help regulate wakefulness, appetite and motivation, mood, energy expenditure and stress-related behaviors. In the study, published Dec. 22, 2022, in Frontiers in Behavioral Neuroscience, the drug strongly reduced voluntary alcohol intake in alcohol-dependent rats, and blocked stress-induced relapse.

These results support the idea of targeting the orexin system for the treatment of alcohol and other substance use disorders, says study senior author Remi Martin-Fardon, PhD, associate professor of Molecular Medicine at Scripps Research.

The study's first author was Francisco Flores-Ramirez, PhD, a postdoctoral research associate in the Martin-Fardon lab.

Alcohol-use disorder, which includes chronic heavy alcohol use and binge drinking, is one of the world's top public health concerns. In the United States alone, it is estimated to affect about 15 million people, killing about 100,000 annually and contributing to a host of health problems, including hypertension, heart disease, dementia and cancers. According to the World Health Organization, more than five percent of the global burden of disease and injury is attributable to alcohol. Treatments include counseling, support groups and drugs such as naltrexone, but most of the time end in relapse.

Over the past decade and a half, studies have implicated orexin signaling in alcoholism and relapse. In humans and other mammals, there are two orexin proteins, orexin-A and orexin-B, which work by binding to distinct orexin receptors on cells throughout the nervous system. Suvorexant blocks the activities of both receptors, and in 2014 became the first orexin-targeting drug to receive U.S. Food and Drug Administration approval though it was developed for treating insomnia.

In the study, Martin-Fardon's team tested suvorexant in rat models of human alcohol dependency and relapse. For the first experiment, they induced dependency by exposing the animals to alcohol vapor 14 hours a day for six weeks. They also trained the rats to self-administer sips of alcohol which the animals did, reliably and at ever-escalating doses whenever the shutoff of the vapor induced withdrawal pangs. Treatment with suvorexant, however, reduced the rats' alcohol use during withdrawal to the same low levels seen in rats that had no alcohol dependency.

Similarly, in rats modeling the stress-induced relapse of alcohol misuse, suvorexant blocked the usual binge-like resumption of alcohol-seeking behavior.

The findings represent further evidence that targeting orexin signaling could be an effective new approach for reducing alcohol misuse. Martin-Fardon notes that study co-author Barbara Mason, PhD, Pearson Family Chair of the Department of Molecular Medicine at Scripps Research, is conducting a clinical trial of the same drug in people with alcohol use disorder.

Martin-Fardon adds that suvorexant and similar insomnia drugs may inhibit alcohol misuse via multiple mechanisms, including reductions in stress, cravings, and sleep disturbances.

These individuals often cannot sleep without resorting to alcohol, so by treating them with an orexin-blocking drug at night, we help them sleep better and hopefully their improved sleep will help reduce the cravings they feel in the daytime, Martin-Fardon says.

He emphasizes that the same strategy could work for other substance use disorders, and his lab currently is studying its effects against prescription opioid dependency.

Alternative use of suvorexant (Belsomra ) for the prevention of alcohol drinking and seeking in rats with a history of alcohol dependence was co-authored by Francisco Flores-Ramirez, Jessica Illenberger, Glenn Pascasio, Alessandra Matzeu, Barbara Mason, and R mi Martin-Fardon, all of Scripps Research during the study.

The research was supported by the National Institute on Alcohol Abuse and Alcoholism (AA026999, AA028549, AA006420, T32 AA007456).

Neurological Disorders Translational Medicine Martin-Fardon, Remi

LINK:	https://www.scripps.edu/news-and-events/press-room/2023/20230110-marti...
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