Summary: Those with PTSD are almost twice as likely to develop alcohol use disorder than their peers who have not experienced trauma. Researchers report drugs that block FKBP5, such as benztropine, a drug used to control symptoms of Parkinson’s disease, and the experimental compound SAFit2 reduce alcohol preference and drinking in models of PTSD.
Source: Scripps Research Institute
Survivors of abuse and trauma are vastly more likely than other people to develop alcohol use disorder (AUD); according to some estimates, as many as three-quarters of people with post-traumatic stress disorder (PTSD) report drinking problems.
Now, Scripps Research scientists have identified a class of drugs that might break this link. In animal models of PTSD, the drug decreased alcohol preference and intake 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 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 U.S. Department of Veterans Affairs National Center for PTSD, about 12 million adults in the U.S. have PTSD during a given year. Men and women who have PTSD at any point in their lives are more than twice as likely as other people to have alcohol abuse or dependence.
Moreover, people who suffer from both PTSD and AUD are at a higher risk of suicidal thoughts and extreme aggression compared to those with 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 the brain’s stress response pathways, and its genetic variants are associated with 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 additional colleagues studied rats with symptoms similar to comorbid human PTSD and AUD. Like people with the disorders, the animals drink more alcohol than average, are irritable and fearful, and exhibit anxiety and sleep disturbances, the team showed.
The researchers treated the animals with either 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 for blocking FKBP5.
They found that benztropine reduced alcohol preference in stressed male and female animals, as well as aggressive behavior in the females. SAFit2 reduced alcohol drinking in stressed males, and decreased levels of extreme fear in both male 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 estrous 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.”
In addition to Roberto, Zorrilla, Cruz and Vozella, authors of the study, “FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder,” include Joy Xu and Dean Kirson of Scripps Research; Benjamin Carper, Shawn Hirsch, Tracy Nolan, Lauren Bradley, Katie Fain and Meg Crawford of RTI International; and Thomas Kosten of Baylor College of Medicine.
Funding: 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 Endowed Chair, and the Department of Defense (DoD).
FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder
Post-traumatic stress disorder (PTSD) leads to enhanced alcohol drinking and development of alcohol use disorder (AUD). Identifying shared neural mechanisms might help discover new therapies for PTSD/AUD.
Here, we employed a rat model of comorbid PTSD/AUD to evaluate compounds that inhibit FK506-binding protein 51 (FKBP5), a co-chaperone modulator of glucocorticoid receptors implicated in stress-related disorders.
Male and female rats received a familiar avoidance-based shock stress followed by voluntary alcohol drinking. We then assessed trauma-related behaviors through sleep bout cycles, hyperarousal, fear overgeneralization, and irritability.
To evaluate the role of stress and alcohol history on the sensitivity to FKBP5 inhibitors, in two separate studies, we administered two FKBP5 inhibitors, benztropine (Study 1) or SAFit2 (Study 2). FKBP5 inhibitors were administered on the last alcohol drinking session and prior to each trauma-related behavioral assessment.
We also measured plasma corticosterone to assess the actions of FKBP5 inhibitors after familiar shock stress and alcohol drinking. Benztropine reduced alcohol preference in stressed males and females, while aggressive bouts were reduced in benztropine-treated stressed females.
During hyperarousal, benztropine reduced several startle response outcomes across stressed males and females. Corticosterone was reduced in benztropine-treated stressed males.
The selective FKBP5 inhibitor, SAFit2, reduced alcohol drinking in stressed males but not females, with no differences in irritability. Importantly, SAFit2 decreased fear overgeneralization in stressed males and females. SAFit2 also reduced corticosterone across stressed males and females. Neither FKBP5 inhibitor changed sleep bout structure.
These findings indicate that FKBP5 inhibitors modulate stress-related alcohol drinking and partially modulate trauma-related behaviors.
This work supports the hypothesis that targeting FKBP5 may alleviate PTSD/AUD comorbidity.