Basal cortisol level modulates stress-induced opioid-seeking behavior

In preclinical studies and our human laboratory, the α₂-noradrenergic autoreceptor antagonist yohimbine was found to promote drug-seeking behavior. This study evaluated effects of dose-combinations of yohimbine and the glucocorticoid receptor agonist hydrocortisone to model intensity-dependent effects of stimulating each neurochemical system, alone and together, on stress-reactivity and opioid-seeking. Twelve regular heroin-using participants diagnosed with opioid use disorder (OUD) were stabilized on sublingual buprenorphine (8-mg/day), then passed a hydromorphone 18-mg vs. placebo intramuscular reinforcement screen. Across 9 experimental conditions (3 × 3 within-subject, randomized crossover, placebo-controlled, double-blind design) during inpatient buprenorphine maintenance, combinations of oral pretreatment doses of yohimbine (0, 27, 54-mg; <i>t</i> = 0 min) then hydrocortisone (0, 20, 40-mg; <i>t</i> = 45 min) were administered. In each condition, subjective drug and mood effects, cardiovascular responses, and saliva cortisol and α-amylase levels were assessed to evaluate stress-reactivity, and participants completed a 12-trial choice progressive ratio task during which they could earn units of hydromorphone (1.5-mg intramuscular) and/or money ($2.00). Yohimbine dose-dependently increased blood pressure, α-amylase, and anxiety scores, and decreased opioid agonist symptoms; hydrocortisone dose-dependently increased cortisol levels. Yohimbine/hydrocortisone dose-combinations significantly shifted within-session responding from money to opioid-seeking among participants with lower basal cortisol levels. These findings replicate yohimbine effects on stress biomarkers and demonstrate that noradrenergic/glucocorticoid-potentiated opioid-seeking is modulated by basal cortisol level. In persons with OUD stabilized on buprenorphine, basal HPA-axis activity and acute stressors can enhance opioid relative reinforcing efficacy. These factors may limit OUD treatment efficacy and highlight the need for novel interventions that prevent stress-induced opioid-seeking.