Endocrine challenge of the HPA axis differentially modulates plasma deoxycortisosterone and pregnenolone levels in cynomolgus monkeys

Deoxycorticosterone (DOC) and pregnenolone (PREG) are precursors of the potent endogenous GABAergic neuroactive steroids allotetrahydrodeoxycorticosterone and allopregnanolone that are increased in rodent brain and plasma after HPA axis activation by acute stress or ethanol administration. However, no data are available for non-human primates. Methods: Eleven adult 4-5 year old male Cynomolgus monkeys were housed individually for 3 months prior to testing. The monkeys had received prior extensive training to comply with awake venipuncture to collect blood for the steroid assays with minimal observable distress. Steroid concentrations were determined by radioimmunoassay in plasma samples from following challenge of the HPA axis with naloxone (375 ug/kg), corticotropin-releasing factor (CRF; 1 ug/kg), dexamethasone (130 ug/kg), or adrenocorticotropic hormone (ACTH; 10 ng/kg) 4-6 hours after 0.5 mg/kg dexamethasone to increase plasma cortisol levels. Ethanol was tested at an intoxicating dose (1.5 g/kg). Results: Naloxone increased DOC and PREG levels by 97 and 216%, respectively, (P<0.001). CRF infusion increased DOC (+50%), but not pregnenolone levels. DOC, but not PREG levels were positively correlated with cortisol or ACTH levels after naloxone challenge. Dexamethasone (130 ug/kg) decreased DOC levels by 42% (P<0.001), but had no effect on PREG levels. ACTH (10 ng/kg) challenge, 4-6 hours after 0.5 mg/kg dexamethasone, did not modify DOC and PREG levels. The effect of dexamethasone challenge on both DOC and PREG levels was highly correlated with subsequent voluntary alcohol drinking. The decrease in DOC levels following dexamethasone was negatively correlated with subsequent alcohol intake (Pearson r = -0.78, P = 0.006, n = 10). Greater suppression of DOC levels was predictive of lower voluntary alcohol consumption. In contrast, dexamethasone-induced changes in PREG levels were positively correlated with subsequent alcohol intake (Pearson r = 0.84, P = 0.001, n = 10). Greater suppression of PREG levels was predictive of higher subsequent alcohol consumption. Ethanol had no effect on DOC or PREG levels in monkey plasma, suggesting that these steroids are differentially regulated in monkeys vs. rats. Discussion: These data show diverse and divergent regulation of GABAergic neurosteroid precursors by HPA axis activation at multiple levels that appears to be related to alcohol drinking behavior in monkeys. Furthermore, since the monkeys had no alcohol exposure prior to the HPA axis challenges, the correlations between subsequent alcohol drinking and DOC and PREG responses to dexamethasone may represent trait markers of propensity to drink alcohol.