'Pharmacotherapies prevent alcohol use disorder in people with PTSD'

SAN DIEGO: Survivors of abuse and trauma are far more prone than other people to acquire alcohol use disorder (AUD); according to some estimates, up to three-quarters of people with post-traumatic stress disorder (PTSD) have drinking issues.

Scripps Research scientists have discovered a class of medications that may be able to break this relationship. In PTSD animal models, the medication reduced alcohol desire and consumption, as well as other PTSD-related characteristics such as aggression, excessive fear, and hyperarousal. The research was published in Neuropsychopharmacology.

"The overlap of PTSD and AUD is a major problem," says co-senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine and a professor of Neuroscience at Scripps Research. "We've shown that there is potential to alleviate both disorders by targeting brain pathways that they share."

According to the National Center for PTSD of the United States Department of Veterans Affairs, approximately 12 million adults in the United States suffer from PTSD in any given year. Men and women who have PTSD at any point in their lives are more than twice as likely as the general population to abuse or become dependent on alcohol. Furthermore, those who have both PTSD and AUD are more likely to have suicidal thoughts and excessive violence than those who only have one of the disorders.

FKBP5, a protein found in the brain, has been linked to both illnesses, according to researchers. The FKBP5 gene is in charge of releasing the brakes on the brain's stress response pathways, and genetic variants of the gene are linked to a higher risk of AUD and PTSD. In animals, higher levels of FKBP5 have been linked to both stress exposure and alcohol exposure.

Co-first authors Bryan Cruz, PhD, and Valentina Vozella, PhD, together with other researchers, evaluated rats exhibiting symptoms similar to comorbid human PTSD and AUD. The animals, like individuals with the diseases, consume more alcohol than the normal person, are irritable and afraid, and suffer from anxiety and sleep difficulties, the researchers discovered.

The animals were given either benztropine (Cogentin), which is FDA-approved to treat Parkinson's disease and targets a number of molecules in the brain, or SAFit2, an experimental compound designed specifically for blocking FKBP5. They found that benztropine reduced alcohol preference in stressed male and female animals, as well as aggressive behaviour in females.

SAFit2 reduced alcohol drinking in stressed males and decreased levels of extreme fear in both males and females. Neither drug impacted sleep. "The results may have varied between male and female animals because of reproductive hormones," says Cruz. "There is new literature suggesting that the activity of these kinds of compounds varies in females throughout the oestrous cycle."

The team says that the fact that benztropine is already FDA-approved suggests the potential for repurposing it in people with PTSD. "We think FKBP5 inhibitors might be useful in preventing AUD after the onset of PTSD," adds co-senior author Eric Zorrilla, PhD, associate professor in the Department of Molecular Medicine. "More work is needed to determine whether these compounds also can prevent the recurrent relapse that hampers recovery."