Differential hypothalamic-pituitary-adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects.

Ethanol and the neuroactive steroids have interactive neuropharmacological effects and chronic ethanol administration blunts the ethanol-induced increase in neuroactive steroid levels in rodent plasma and brain. Few studies have explored neuroactive steroid regulation in alcohol-dependent human subjects. In fact, the regulation of adrenal neuroactive steroids has not been well defined in healthy controls. We thus explored the regulation of two neuroactive steroids, pregnenolone sulfate (PREG-S) and deoxycorticosterone, by pharmacological challenges to the hypothalamic-pituitary-adrenal (HPA) axis in healthy controls and 1-month abstinent alcohol-dependent patients with co-occurring nicotine dependence. Plasma levels of PREG-S and deoxycorticosterone were measured by radioimmunoassay in controls and alcohol-dependent patients after challenges of naloxone, ovine corticotrophin releasing hormone (oCRH), dexamethasone, cosyntropin, and cosyntropin following high-dose dexamethasone. In addition, basal diurnal measures of both hormones were obtained. PREG-S plasma levels in healthy controls were increased by cosyntropin challenge (with and without dexamethasone pretreatment) and decreased by dexamethasone challenge. However, PREG-S concentrations were not altered by naloxone or oCRH challenges, suggesting that PREG-S is not solely regulated by hypothalamic or pituitary stimulation. Deoxycorticosterone, in contrast, is regulated by HPA challenge stimulation in a manner similar to cortisol. Alcohol-dependent patients had a blunted PREG-S response to cosyntropin (with and without dexamethasone pretreatment). Furthermore, the time to peak deoxycorticosterone response following oCRH was delayed in alcohol-dependent patients compared to controls. These results indicate that plasma PREG-S and deoxycorticosterone levels are differentially regulated by HPA axis modulation in human plasma. Further, alcohol-dependent patients show a blunted PREG-S response to adrenal stimulation and a delayed deoxycorticosterone response to oCRH challenge.