Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

Abstract

Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol-and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucroseseeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanolseeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals

“…Mifepristone (n = 5/group; dose × group interaction: F 2,16 = 4.044, P = 0.0379) at 10 μg/side (P = 0.0068) and 30 μg/side (P = 0.0280), significantly and specifically reduced alcohol intake in dependent rats, when compared with vehicle (0 μg/side) controls ( Figure 1D). Our demonstration of increased GR phosphorylation during dependence and reduction of compulsive-like alcohol drinking by intra-CeA mifepristone injection, combined with previous findings (19), indicate that increased GR signaling in the CeA plays a functional role in alcohol drinking and seeking.…”

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

“…Gabapentin reduced both the anxiogenic-like behavior and the increased ethanol self-administration observed in withdrawn, ethanol dependent rats, but not non-dependent rats (Roberto et al 2008; Besheer et al 2016; Watson et al 1997) and was found to improve emotional function and reduce insomnia and alcohol use in abstinent alcoholics (Bonnet et al 2007; Malcolm et al 2007; Brower et al 2008; Myrick et al 2009; Mason et al 2014). Most recently, the glucocorticoid receptor antagonist mifepristone, which like CRF 1 antagonists more efficaciously reduces ethanol intake in dependent rodents during abstinence than in non-dependent rodents (Yang et al 2008; Simms et al 2012; Vendruscolo et al 2012; Vendruscolo et al 2015), was found to reduce alcohol-cued craving in the laboratory as well as naturalistic measures of alcohol use in a double-blind, placebo-controlled study of 56 alcohol-dependent human subjects (NCT01548417; Vendruscolo et al 2015). Thus, the preclinical models do show predictive sensitivity to detect effective treatments.…”

The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

“…The glucocorticoid receptor antagonist mefipristone is a promising therapeutic, which when administered systemically or locally into the central amygdala (CeA), reduced yohimbine-stress induced reinstatement of ethanol seeking in male Long-Evans rats (Simms et al, 2012) and when given systemically reduced alcohol self-administration in alcohol dependent Wistar rats (Vendruscolo et al, 2015). In a recent study, mefipristone reduced alcohol-cued craving and self-reported alcohol consumption in 56 alcohol-dependent, outpatient human volunteers who had been abstinent for 3 days before the alcohol cue laboratory session (Vendruscolo et al, 2015).…”