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FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder

Abstract

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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Fig. 1: Experimental design overview.
Fig. 2: FKBP5 inhibitors reduce alcohol drinking after familiar shock stress history.
Fig. 3: Selective inhibition of FKBP5 reduces fear overgeneralization after familiar shock stress and alcohol drinking history.
Fig. 4: Benztropine reduces aggressive bouts after familiar shock stress and alcohol drinking in females.
Fig. 5: FKBP5 inhibitors suppress plasma corticosterone after familiar shock stress and alcohol drinking.

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Acknowledgements

The authors thank Dr. Luisa B. Bertotto for her technical support with experiments and Shannon R. D’Ambrosio for assisting during shock stress procedures.

Funding

Support for this study was provided by The National Institute on Alcohol Abuse and Alcoholism grants, AA027700, AA028879, AA013498, P60 AA006420, AA017447, AA021491, AA029841, AA015566, K99 AA026638, T32 AA007456, and the Schimmel Family Endowed Chair. The Department of Defense (DoD) provided support for the Pharmacotherapies for Alcohol and Substance use disorders Alliance (PASA). The Alcohol and Substance Use Disorders Research Program (ASUDRP) Programmatic Panel is a Department of Defense (DoD) appointed and chaired steering committee that provides oversight to the PASA Consortium. The ASUDRP Programmatic Panel is chaired by DoD and comprises government representatives and non-DoD subject matter experts. The panel approves all studies to be conducted, recommends new studies, and identifies existing and new requirements as they arise. The ASUDRP Programmatic Panel is the overall main governing and management committee and the committee through which the DoD interacts and collaborates with the PASA Consortium. The ASUDRP Programmatic Panel determines all major scientific decisions; clinical studies proposed by the Consortium Committee proceed into the implementation stage only with the approval of the ASUDRP Programmatic Panel. While the DoD/ASADRP had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of DoD, ASUDRP, or the U.S. Government. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Alcohol and Substance Use Research Program under Award No. W81XWH1820044. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. In conducting research using animals, the investigator(s) adhered to the laws of the United States and regulations of the Department of Agriculture. Data were collected at participating sites of the PASA consortium and were transmitted to RTI International for this study. RTI International has full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. This is manuscript number 30175 from The Scripps Research Institute.

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BC, VV, EPZ, and MR designed and conceived the project. BC and VV collected behavioral and blood plasma data. BC, BAC, and SH analyzed behavioral data. BC and VV analyzed the blood plasma data. BC, VV, EPZ, and MR drafted the figures and manuscript. BC, VV, BAC, JCX, DK, SH, TN, LB, KF, MC, TRK, EPZ, and MR commented and edited the manuscript.

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Correspondence to Eric P. Zorrilla or Marisa Roberto.

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Cruz, B., Vozella, V., Carper, B.A. et al. FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01497-w

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