New findings on the role of neuroactive steroids and HPA axis in alcohol addiction - results from animal studies

The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathology of alcoholism; however, its mechanisms are not completely understood. A blunted HPA axis response has been found in rodent models of alcohol dependence and in both drinking and abstinent alcohol dependent patients. However, it is not yet clear if this blunted response involves a genetic component or if it is subsequent to excessive alcohol consumption. Furthermore, the HPA axis response to acute ethanol administration appears to differ among species, with rodents and humans showing activation of the axis after intoxication and non-human primates lacking this response. We studied HPA axis regulation of the neuroactive steroid deoxycorticosterone in ten adult cynomolgus monkeys, before and after voluntary alcohol consumption. Pharmacological challenges with naloxone, saline, corticotrophin releasing factor (CRF), dexamethasone, and adrenocorticotropic hormone (ACTH) after dexamethasone were conducted prior to and following twelve consecutive months of ethanol self-administration. Deoxycorticosterone concentrations were measured by radioimmunoassay in plasma samples. Basal deoxycorticosterone levels were elevated by 244% (p<0.001) following long-term alcohol self-administration. Deoxycorticosterone responses to CRF (1 microg/kg, i.v.) and dexamethasone (130 microg/kg, i.m.) challenges were blunted, while responses to ACTH (10 ng/kg, i.v.) challenge were enhanced. The effect of naloxone challenge (375 microg/kg, i.m.) on deoxycorticosterone response was not altered by long-term ethanol exposure. These data suggest that long-term ethanol self-administration alters baseline and HPA-mediated plasma deoxycorticosterone responses in monkeys. Furthermore, we found that dexamethasone suppression of plasma deoxycorticosterone levels in ethanol-naïve cynomolgus monkeys is negatively correlated with subsequent voluntary ethanol intake (Pearson's r = -0.78, p=0.006). Monkeys that drank the most alcohol exhibited weaker suppression of DOC levels by dexamethasone. This correlation was lost after long-term voluntary alcohol consumption. The data suggest that deoxycorticosterone sensitivity to dexamethasone may represent a predictive marker of heavy drinking. Furthermore, the adaptations in HPA-mediated deoxycorticosterone responses after long-term voluntary alcohol consumption might shed new light in understanding alcohol dependence mechanisms.