FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder
Open accessAbstract
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.
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FKBP5 inhibitors are now being explored in clinical trials for PTSD and alcohol use disorder.
“These insights have driven the development of FKBP5 inhibitors, which are now being explored in clinical trials for PTSD and alcohol use disorder”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [48]
The Introduction describes testing two FKBP5 inhibitors in rats, and the Discussion reports reduced alcohol drinking and some trauma-related behaviors in that model. The Discussion proposes further investigation for comorbid PTSD and alcohol use disorder, but does not report that FKBP5 inhibitors are being explored in clinical trials. (LLM, conf=0.88)
Experimental — accuracy not yet measuredStudies employing ATAC-seq have revealed increased accessibility of glucocorticoid-responsive enhancers in the brains of stressed individuals.
“Studies employing ATAC-seq have revealed increased accessibility of glucocorticoid-responsive enhancers in the brains of stressed individuals”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [48]
The Introduction reports increased FKBP5 expression in brain regions after stress, and the Methods describe behavioral testing and plasma corticosterone analysis in rats. Our copy does not report ATAC-seq or increased accessibility of glucocorticoid-responsive enhancers; searches for those terms and for chromatin accessibility found no supporting passage. (LLM, conf=0.76)
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- Authors
- Cruz, B., Vozella, V., Carper, B. A., Xu, J. C., Kirson, D., Hirsch, S., Nolen, T., Bradley, L., Fain, K., Crawford, M., Kosten, T. R., Zorrilla, E. P., & Roberto, M.
- Affiliations
- Scripps Research Institute (US)
- RTI International (US)
- Baylor College of Medicine (US)
- Corresponding author
- Zorrilla, Eric P.
- Roberto, Marisa
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2022-11-18
- Volume
- 48
- Issue
- 8
- Pages
- 1144-1154
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC10267127
- OpenAlex
- W4309437275
- Cited by
- 25
- References
- 68
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 1
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (T32 AA007456, K99 AA026638, AA028879, AA027700, AA013498, P60 AA006420, AA017447, AA021491, AA029841, AA015566)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- post-traumatic stress disorder, alcoholism, benztropine, glucocorticoid receptor, shock stress, alcohol preference, hyperarousal, startle response, corticosterone, irritability, sex differences
- MeSH terms
- Alcohol Drinking, Alcoholism, Animals, Benztropine, Corticosterone, Male, Stress Disorders, Post-Traumatic, Comorbidity, Tacrolimus Binding Proteins, Rats
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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