LA JOLLA, CA—An experimental antidepressant compound with a potentially unique mechanism of action may also be effective against alcohol use disorder, according to a preclinical study from Scripps Research.
In the study, which appeared Jan. 20, 2023, in Neuropsychopharmacology, researchers found that several weeks of treatment with the molecule MAP4343 reversed excessive alcohol intake in mice that modeled this condition.
MAP4343, a steroid-type molecule, is currently being investigated in clinical trials as an antidepressant, though its probable mechanism of action—which involves modulating structural proteins in cells—is unlike that of any other antidepressant or alcohol use disorder treatment.
"These promising results suggest that we should test MAP4343 in people as a potential treatment for alcohol use disorder," says study senior author Candice Contet, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.
The first author was Giovana Macedo, PhD, a postdoctoral research associate in the Contet lab during the study.
Researchers estimate that more than 100 million people around the world have an alcohol use disorder, and that it accounts for more than five percent of the total global burden of disease and injury. There is a strong need for better treatments since current options, which include the drug naltrexone, usually fail to prevent a relapse.
Traditionally, researchers have sought to treat alcohol use disorder by blocking the rewarding effects of drinking alcohol—as naltrexone does—or by reversing the anxiety and malaise that arise after alcohol withdrawal and promote relapse. However, recent studies of rodent and human brains have found evidence that alcohol use disorder can disrupt the normal production and/or regulation of key structural proteins in brain cells. These proteins include tubulin, the chief constituent of structures called microtubules, which cells use for a variety of functions including cell division and the internal transport of molecules. Precisely how disruptions to tubulin and microtubules relate to alcohol use isn't yet clear, but the available evidence suggests that these disruptions help sustain alcohol dependency—so that reversing them could offer a more effective treatment strategy.
MAP4343 plausibly could fill this treatment role, since it is known to promote the assembly of tubulin proteins into microtubules. Preclinical studies also have found that MAP4343 has antidepressant properties, and its developer MAPREG, a French biotech company, is now testing it in clinical trials in patients with depression.
In the new study, the team tested MAP4343 on mice that modeled alcohol use disorder. In this standard model, intermittent exposure to alcohol vapor creates a state of dependency, such that the animals consume more and more alcohol when given a happy hour-like opportunity to drink every day—and within a few weeks are getting to D.U.I. levels of intoxication voluntarily. However, when treated for six weeks with escalating doses of MAP4343, alcohol-dependent mice reduced their average daily consumption to around the levels seen in non-dependent control mice, which were relatively unaffected by the treatment. MAP4343 also normalized blood levels of the stress hormone corticosterone, which are lower in alcohol-dependent animals forced to abstain from alcohol drinking.
Contet and her colleagues conclude that MAP4343 should also be clinically tested against alcohol use disorder.
Understanding MAP4343's precise mechanism of action is another key remaining goal. In this study, the researchers found that alcohol-dependent mice experiencing alcohol withdrawal have unusually low levels of a modified form of tubulin (called acetylated α-tubulin) in the medial prefrontal cortex. This brain region is known to help regulate alcohol consumption and is often weakened in alcohol use disorder.
"Tubulin acetylation is known to change the mechanical properties of microtubules and it is possible that MAP4343 works against excessive alcohol drinking by reversing this change," Contet says. "That is something we now intend to investigate."
"Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder" was co-authored by Giovana Macedo, Max Kreifeldt, Scott Goulding, Agbonlahor Okhuarobo, Harpreet Sidhu, and Candice Contet, all of Scripps Research.
The research was funded in part by the National Institutes of Health (AA006420, AA026685, AA027636, AA027372).
About Scripps Research
Scripps Research is an independent, nonprofit biomedical institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.
