Drug study could bring new treatment for alcohol use disorder

A University of Toledo neuroscientist who studies substance abuse and addiction is leading a new federally funded research project to further develop an experimental drug that could reduce cravings and lessen withdrawal symptoms when chronic drinkers attempt to get sober.

"Alcohol is widely available and very much a part of our culture, but it's also an extremely addictive substance," said Dr. Youssef Sari, a professor in the UToledo College of Pharmacy and Pharmaceutical Sciences. "Alcohol abuse and addiction are both serious problems in this country. Once you are addicted, it's really hard to quit."

Sari has dedicated his career to studying how alcohol and other drugs affect the brain and hijack our reward system, with a goal of finding new therapeutics that can aid in recovery.

His recent work on the role of glutamate transmission as a potential drug target has earned him a five-year, $2.2 million grant from the National Institute on Alcohol Abuse and Alcoholism.

A neurotransmitter that sends stimulating signals throughout our brain, glutamate is essential for normal brain function, particularly the processes of learning and memory.

"Glutamate is an excitatory chemical messenger," said Sari, who also serves as vice chair of the Department of Pharmacology and Experimental Therapeutics. "When you have too much glutamate it's going to overstimulate the neurons and trigger cravings for alcohol."

Chronic drinking reduces a regulatory protein in the brain called glutamate transporter 1 (GLT-1), which allows glutamate levels to rise. In addition to fostering addiction, high levels of glutamate can lead to neurotoxicity.

Sari's focus has been on finding a way to increase the brain's supply of GLT-1, which in turn can lower glutamate levels and suppress the desire to drink.

A decade ago, Sari showed that ceftriaxone, an antibiotic commonly used to treat bacterial meningitis, was able to increase GLT-1 levels in rats. The increase in GLT-1 corresponded to lower glutamate levels and a reduction in their desire to consume alcohol.

Ceftriaxone wasn't itself a viable option for treating alcohol addiction, in part over concerns about overuse of the drug promoting antibiotic-resistant bacteria, but the discovery has launched a line of additional research, including the new federally funded project.

In that work, Sari is collaborating with Dr. Magid Abou-Gharbia, a well-known Temple University scientist and drug developer, to test a novel beta lactam drug that has the same action as ceftriaxone but isn't an antibiotic.

"He had seen my research and contacted me to say, 'You have a good target. I have a good compound. Let's work together,'" Sari said. "He was persistent about working together and we really complement each other on this project."

Sari, Abou-Gharbia and their colleagues have already published initial research about the new drug, showing it was successful in reducing drinking behavior and normalizing levels of GLT-1 in rats.

The drug also normalized GLT-1 expression in the liver and reduced alcohol-induced increases in fat droplet content in the liver, suggesting it could not only help with alcohol cravings, but might also help with liver injury caused by heavy drinking.

With the new grant, the research team will look to build a deeper understanding of the drug and how it works in the body, including how it is metabolized and the specific way it works on its target.

They'll also create and test a library of similar molecules for efficacy and safety with a goal of identifying one lead compound that could be advanced toward a phase 1 clinical trial in humans.

While there are three medications currently approved by the U.S. Food and Drug Administration for treating alcohol use disorder, Sari said they don't always work.

"The other medications hit the receptor, but they don't change the expression. They're just helping temporarily with the symptoms but not bringing the expression back to normal," Sari said. "My drug will change the expression, and that's really important. If we're successful with this, we will have a new therapeutic option that can be helpful in getting people through the process of rehabilitation."

Provided by University of Toledo