Selective Glucocorticoid Receptor Antagonism in Alcohol Use Disorder: A Human Neuroscience Study

ABSTRACT/SUMMARY Perturbations of the hypothalamic-pituitary-adrenal (HPA) axis characterize alcohol use disorder (AUD). The HPA axis is the primary stress-response system and cortisol is the major adrenal glucocorticoid hormone in most mammals. A negative feedback system involving glucocorticoid receptors (GRs) regulates HPA axis activity and cortisol secretion. Preclinical studies have shown glucocorticoid receptor (GR) antagonists reduce alcohol (ALC) reward, withdrawal, and stress-induced relapse in preclinical studies. Despite this robust literature, these areas are understudied in humans, perhaps because the only clinically available GR antagonist, mifepristone, is not selective. The proposed rigorous crossover study will translate provocative preclinical findings implicating GRs in AUD to humans using a selective GR antagonist, PT150. Participants (N=34, 17 females, 17 males) will complete an experimental session after at least 5 days of maintenance on each PT150 dose (0, 450, 900 mg/day) to determine responses to experimentally induced stress. Participants will complete a separate experimental session to determine if PT150 attenuates the pharmacodynamic effects of ALC (0.5 g/kg). We will record behavioral (i.e., ALC demand, craving, mood, and subjective effects), neuroendocrinological (i.e., cortisol), and physiological (i.e., heart rate, blood pressure, breath ALC level) responses before stress or ALC, and periodically afterwards for 120 mins. Finally, we will determine whether PT150 reduces ALC use (i.e., number of drinks and heavy drinking days/week), craving, and stress in the natural ecology. We predict: 1) stress induction will increase cortisol, ALC demand and negative mood and PT150 will attenuate these responses, 2) ALC will increase ALC demand and produce prototypical subjective effects and PT150 will attenuate these effects, and 3) PT150 will decrease drinking, craving, and stress in the natural ecology. Exploratory aims will determine if: 1) responses/changes differ in females and males; 2) baseline cortisol or stress levels will predict behavioral or neuroendocrinological responses to stress and attenuation by PT150; and 3) behavioral and neuroendocrine responses and attenuation by PT150 during the stress-induction session predict changes in the naturalistic ecology. This project will expand the scope of clinical neuroscience research on AUD by focusing on GR antagonism in humans. Rigorous preclinical research supports this proposal. The proposed research could provide the impetus for subsequent clinical research to develop PT150 as an adjunct therapy for AUD. Because HPA dysregulation occurs in stimulant, opioid, and tobacco use disorders, this project could also spur interest in elucidating the role of GR antagonism in other substance use disorders. The proposed work will produce an immediate and sustained impact.