Studies of HPA axis function provide insights into the mechanisms underlying alcoholism risk. We have found that dexamethasone suppression of plasma deoxycorticosterone (DOC) 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. The data suggest that DOC sensitivity to dexamethasone may represent a predictive marker of heavy drinking. We have extended this finding to the BXD parental mouse strains, C57BL/6J and DBA/2J that show opposite drinking phenotypes. Mice were injected with three doses of dexamethasone (0.075, 0.1 and 0.13 mg/kg, sc) or saline at 8:00am and were sacrificed 6 hours later. Plasma DOC levels in DBA/2J mice were decreased by 61, 55 and 58%, at 0.075, 0.1 and 0.13 mg/kg, respectively (p<0.001). In contrast, plasma DOC levels in C57BL/6J mice were not altered by administration of dexamethasone 0.075 and 0.1 mg/kg; only the dose of 0.13 mg/kg induced a significant decrease (-62%, p<0.05). These results suggest that C57BL/6J and DBA/2J mice differ in their sensitivity to dexamethasone suppression of plasma DOC levels in a manner that relates to drinking behavior. Similar to monkeys, the high drinking C57BL/6J mice show a weaker dexamethasone suppression of DOC. We are now investigating dexamethasone suppression of DOC and other neuroactive steroids in different monkeys and BXD mouse strains. These results may identify new biomarkers of alcoholism risk.
Identification of neuroactive steroid biomarkers of alcohol consumption in monkeys and mice
Porcu P;
2008
Abstract
Studies of HPA axis function provide insights into the mechanisms underlying alcoholism risk. We have found that dexamethasone suppression of plasma deoxycorticosterone (DOC) 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. The data suggest that DOC sensitivity to dexamethasone may represent a predictive marker of heavy drinking. We have extended this finding to the BXD parental mouse strains, C57BL/6J and DBA/2J that show opposite drinking phenotypes. Mice were injected with three doses of dexamethasone (0.075, 0.1 and 0.13 mg/kg, sc) or saline at 8:00am and were sacrificed 6 hours later. Plasma DOC levels in DBA/2J mice were decreased by 61, 55 and 58%, at 0.075, 0.1 and 0.13 mg/kg, respectively (p<0.001). In contrast, plasma DOC levels in C57BL/6J mice were not altered by administration of dexamethasone 0.075 and 0.1 mg/kg; only the dose of 0.13 mg/kg induced a significant decrease (-62%, p<0.05). These results suggest that C57BL/6J and DBA/2J mice differ in their sensitivity to dexamethasone suppression of plasma DOC levels in a manner that relates to drinking behavior. Similar to monkeys, the high drinking C57BL/6J mice show a weaker dexamethasone suppression of DOC. We are now investigating dexamethasone suppression of DOC and other neuroactive steroids in different monkeys and BXD mouse strains. These results may identify new biomarkers of alcoholism risk.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
