Survivors of abuse and trauma are more likely than others to develop an alcohol use disorder (AUD); According to some estimates, up to three-quarters of people with post-traumatic stress disorder (PTSD) have a drinking problem.
Now, Scripps research scientists have identified a class of drugs that may break this link. In animal models of PTSD, the drug reduced alcohol preference and intake as well as other behaviors associated with PTSD, including aggressiveness, excessive fear, and hyperarousal. The results are published in Neuropsychopharmacology On November 18, 2022.
“The overlap between PTSD and AUD is a huge problem,” says co-author Marisa Roberto, PhD, chair of the Schimmel Family of Molecular Medicine and professor of neuroscience at Scripps Research. “We have shown that there is potential for alleviating both disorders by targeting brain pathways that are common to both.”
According to the Department of Veterans Affairs National Center for Post-Traumatic Stress Disorder, approximately 12 million adults in the United States experience PTSD during a given year. Men and women who experience PTSD at any time in their lives are twice as likely to be addicted to or dependent on alcohol. Furthermore, people with PTSD and AUD are at greater risk of suicidal thoughts and extreme aggressiveness compared to those without either disorder alone.
Researchers have known that FKBP5, a protein found in the brain, plays a role in both disorders. The FKBP5 gene is responsible for lifting the brakes on stress response pathways in the brain, 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, first co-authors Brian Cruz, PhD, Valentina Fuzzella, PhD, and other colleagues studied rats showing similar symptoms of post-traumatic stress disorder (PTSD) and post-traumatic stress disorder (AUD). The team showed that the animals, like people with the disorder, drink more alcohol than average, are nervous and fearful, and show anxiety and sleep disturbances. The researchers treated the animals with either of two drugs known to target FKBP5: benztropine (Cogentin®), which is FDA-approved for the treatment of Parkinson’s disease and targets a number of molecules in the brain, or SAFit2, an experimental compound specifically designed to block FKBP5. FKBP5.
They found that benztropine reduced alcohol preference in both male and female stressed animals, as well as aggressive behavior in females. SAFit2 reduced alcohol drinking in stressed males, and reduced levels of extreme fear in both males and females. Both medications did not affect sleep.
“The results may have differed between male and female animals due to reproductive hormones,” Cruz says. “There is new literature indicating that the activity of these types of compounds varies in females throughout the esterification cycle.”
The fact that benztropine has already been approved by the FDA, the team says, indicates potential for reuse in people with PTSD.
“We believe that FKBP5 inhibitors may 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 can also prevent recurrent relapse that impairs 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), and the Schimmel Family Department of Defense (Do, Granted Chief).