# Central amygdala Fkbp5 expression correlates with faster submission and ethanol self-administration reacquisition: Benztropine reduces ethanol relapse-like reacquisition in stressed rats

## TL;DR

This study shows that Fkbp5 in the amygdala is linked to faster stress submission and alcohol relapse in rats, and benztropine may help reduce relapse after stress.

## Contribution

The study identifies a novel role for CeA Fkbp5 in stress-induced ethanol relapse and shows benztropine's potential as a treatment.

## Key findings

- CeA Fkbp5 expression correlates with faster submission to stress and increased ethanol reacquisition.
- Benztropine reduces ethanol relapse-like behavior in stressed rats in a dose-dependent manner.
- Sex-specific effects suggest benztropine may be more effective in male rats.

## Abstract

Stress-related emotional disorders, such as post-traumatic stress disorder (PTSD) and major depression, increase alcohol relapse risk. PTSD, depression, and alcohol use phenotypes associate with gene variants of FKBP prolyl isomerase 5 (FKBP5), a chaperone modulator of glucocorticoid receptors (GR). FKBP51 inhibitors can decrease ethanol intake, but FKBP51's role in recurrence of post-stress ethanol drinking is unknown. We tested the hypotheses that expression of Fkbp5 and immediate early genes (IEGs) in the central nucleus of the amygdala (CeA) is increased in rats with a history of defeat or foot-shock stress and associates with faster submission and increased reacquisition of ethanol self-administration. We tested if benztropine mesylate, an FDA-approved drug that inhibits FKBP51-GR binding, reduces reacquisition of ethanol self-administration in rats with a history of foot-shock stress. Wistar rats were studied after resident-intruder social defeat (n = 32) or in an ethanol self-administration reacquisition model, with or without repeated foot-shock history (n = 62). Acute social defeat stress increased CeA IEG expression within 1 h Fkbp5 expression by 6 h. CeA IEG activation correlated with Fkbp5 expression, and both correlated with faster submission to defeat. CeA Fkbp5 expression also associated with greater ethanol intake and blood ethanol concentration during reacquisition of ethanol self-administration. Benztropine (i.p., 5, 10 mg/kg) dose-dependently reduced relapse-like ethanol reacquisition, and sex-specific analyses suggest a more robust effect in males than females. The results warrant the study of CeA FKBP51 in passive stress coping and of drug-like selective FKBP51 inhibitors to reduce ethanol relapse after histories of repeated stress.