Abuse and trauma survivors are much more likely than others to develop alcohol use disorder (AUD); by some estimates, up to three-quarters of people with post-traumatic stress disorder (PTSD) report alcohol problems.
Now Scripps Research scientists have identified a class of drugs that could break that link. In animal models of PTSD, the drug decreased alcohol preference and consumption as well as other behaviors associated with PTSD, including aggression, excessive fear, and hyperarousal. The findings were published in Neuropsychopharmacology on November 18, 2022.
“The overlap of PTSD and AUD is a major issue,” says co-lead author Marisa Roberto, PhD, Schimmel Family Chair in Molecular Medicine and professor of neuroscience at Scripps Research. “We have shown that there is potential to alleviate both disorders by targeting the brain pathways they share.”
According to the US Department of Veterans Affairs’ National Center for PTSD, approximately 12 million adults in the United States suffer from PTSD in any given year. Men and women who suffer from PTSD at any point in their life are more than twice as likely as others to suffer from alcohol abuse or dependence. Additionally, people who have both PTSD and AUD are at higher risk for suicidal thoughts and extreme aggression than those with either disorder alone.
Researchers know that FKBP5, a protein found in the brain, plays a role in both disorders. The FKBP5 gene is responsible for removing the brakes on the brain’s stress-response pathways, and its genetic variants are associated with an increased risk of AUD and PTSD. In animals, higher levels of FKBP5 have been linked to both stress exposure and alcohol exposure.
In the new study, co-first authors Bryan Cruz, PhD, and Valentina Vozella, PhD, and other colleagues studied rats with symptoms similar to comorbid human PTSD and AUD. Like people with the disorder, the animals drink more alcohol than average, are irritable and fearful, and exhibit anxiety and trouble sleeping, the team showed. The researchers treated the animals with one of two drugs known to target FKBP5: 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 to block FKBP5.
They found that benztropine reduced the preference for alcohol in stressed male and female animals, as well as aggressive behavior in females. SAFit2 reduced alcohol consumption in stressed men and decreased levels of extreme fear in both men and women. Neither drug had any impact on sleep.
“Results may have varied between male and female animals due to reproductive hormones,” says Cruz. “There is new literature suggesting that the activity of these types of compounds varies in women throughout the estrous cycle.”
The team says the fact that benztropine is already FDA-approved suggests the possibility of its reuse in people with PTSD.
“We believe that FKBP5 inhibitors may be useful in preventing AUD after the onset of PTSD,” adds co-lead author Eric Zorrilla, PhD, associate professor in the Department of Molecular Medicine. “Further work is needed to determine whether these compounds can also prevent recurrent relapses that impede recovery.”
Support for this study was provided by the National Institute on Alcohol Abuse and Alcoholism (AA027700, AA028879, AA013498, P60 AA006420, AA017447, AA021491, AA029841, AA015566, K99 AA026638 and T32 AA007456), the Schimmel Family Department of Defense (DoD).