Benztropine Reduces Reacquisition of Alcohol Self‐Administration in Rats with Stress History: Role of FKBP5

Post-traumatic stress disorder (PTSD), which can affect 1 in 11 adults during their lifetime, is often comorbid with chronic alcohol use problems and increases alcohol relapse risk. PTSD and alcohol-use phenotypes are associated with variants in the FKBP propyl isomerase 5 (FKBP5) gene, which encodes FK506-binding protein 5 (FKBP5), a chaperone modulator of glucocorticoid receptors (GR) that is functionally implicated in stress-related psychiatric disorders and alcohol withdrawal severity. Data suggests that FKBP5 inhibition may decrease alcohol intake, but its role in the post-traumatic recurrence of alcohol drinking is unknown. Here, we tested the hypotheses that amygdala Fkbp5 expression is increased in rats with a history of traumatic stress and is associated with greater reacquisition of ethanol self-administration. Then, we tested the hypothesis that benztropine mesylate, an FDA-approved drug that disrupts FKBP5-GR binding, reduces reacquisition of ethanol self-administration in rats with a history of traumatic stress. Separate cohorts (for mRNA vs. benztropine studies) of male (n = 43) and female (n = 20) Wistar rats received 3 sessions of light-cued footshock stress (30 min session, 60 footshocks, 1-s 0.4 mA) before acquiring operant ethanol (10% v/v) self-administration (1-h sessions, fixed ratio1-3), followed by extinction (16 sessions), and then renewed alcohol access. Amygdala Fkbp5 expression correlated significantly with increased ethanol self-administration (rs (23) = 0.463, p = 0.023) during renewal of ethanol access. Subchronic (3 days) benztropine pretreatment (-2 h, i.p., 0, 5, and 10 mg/kg [n = 10, 14, and 14]) significantly reduced the reacquisition of ethanol self-administration. On days 2 and 3 of reacquisition, self-administration was significantly reduced in drug treated animals (Dose x Day: F(4,64)=2.83, p < 0.04), culminating in a 68% reduction in males (0.78±0.16 vs. 0.25±0.13 g/kg) and a 41% reduction in females (0.88±0.14 vs. 0.52±0.13 g/kg) at the 10 mg/kg dose. Overall, the results warrant further study of benztropine and its potential inhibition of FKBP5 to reduce post-traumatic alcohol relapse risk.