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

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 (<i>FKBP5</i>), 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 <i>Fkbp5</i> 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 (<i>n</i> = 32) or in an ethanol self-administration reacquisition model, with or without repeated foot-shock history (<i>n</i> = 62). Acute social defeat stress increased CeA IEG expression within 1 h <i>Fkbp5</i> expression by 6 h. CeA IEG activation correlated with <i>Fkbp5</i> expression, and both correlated with faster submission to defeat. CeA <i>Fkbp5</i> 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.