Studies of hypothalamic-pituitary-adrenal 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 correlated with subsequent voluntary ethanol intake: monkeys who are insensitive to dexamethasone drink the most alcohol in a two bottle self-administration paradigm, suggesting that DOC insensitivity to dexamethasone may represent a predictive marker of heavy drinking. Furthermore, dexamethasone suppression of plasma and cerebral cortical DOC levels is differentially regulated in C57BL/6J and DBA/2J mice. C57BL/6J mice consume large amounts of ethanol in a two bottle choice paradigm and show a blunted dexamethasone suppression of DOC, compared to DBA/2J mice that consume less alcohol. DOC sensitivity to dexamethasone was tested across the BXD recombinant inbred mice which allow us to model the genetic variability known to exist in the human population. Mice were injected with 0.075 mg/kg dexamethasone sodium salt or saline at 8:00am and were sacrificed 6 hours later. DOC levels were measured in plasma and cerebral cortex by radioimmunoassay. We found genetic variation in basal DOC levels measured following saline administration in both plasma and cerebral cortex. Plasma DOC levels across 35 BXD strains range between 2.8 and 12.1 ng/ml, resulting in a 4.3-fold variation. Cerebral cortex DOC levels across 24 strains range between 2.5 and 12.2 ng/g, resulting in a 4.9-fold variation. A correlation between plasma vs. cerebral cortical basal levels across these strains was observed (Spearman r=0.77, p<0.0001, n=26). Suggestive quantitative trait loci (QTLs) for basal DOC levels were found on chromosomes 4 and 17. The dexamethasone-induced changes in DOC levels showed a 3.4-fold variation in plasma across 35 BXD strains and a 4.2-fold variation in cerebral cortex across 24 strains. A correlation between dexamethasone-induced changes in plasma vs. cerebral cortex DOC levels was observed (Spearman r=0.66, p=0.0002, n=26). Suggestive QTLs for the dexamethasone-induced changes in plasma and cerebral cortical DOC levels were found on chromosomes 1, 2, 3, 7 and 13. Finally, variations in basal and dexamethasone-induced changes in plasma and cerebral cortical DOC levels were correlated with several ethanol and anxiety behavioral phenotypes using public data sets on GeneNetwork.org. The results suggest that DOC and dexamethasone effects on DOC levels may represent neuroendocrine biomarkers for alcohol and/or anxiety phenotypes in mice that could potentially persist across different species.
Dexamethasone suppression of deoxycorticosterone across the BXD recombinant inbred mice: A putative neuroactive steroid biomarker for alcohol and anxiety phenotypes
Porcu P;
2009
Abstract
Studies of hypothalamic-pituitary-adrenal 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 correlated with subsequent voluntary ethanol intake: monkeys who are insensitive to dexamethasone drink the most alcohol in a two bottle self-administration paradigm, suggesting that DOC insensitivity to dexamethasone may represent a predictive marker of heavy drinking. Furthermore, dexamethasone suppression of plasma and cerebral cortical DOC levels is differentially regulated in C57BL/6J and DBA/2J mice. C57BL/6J mice consume large amounts of ethanol in a two bottle choice paradigm and show a blunted dexamethasone suppression of DOC, compared to DBA/2J mice that consume less alcohol. DOC sensitivity to dexamethasone was tested across the BXD recombinant inbred mice which allow us to model the genetic variability known to exist in the human population. Mice were injected with 0.075 mg/kg dexamethasone sodium salt or saline at 8:00am and were sacrificed 6 hours later. DOC levels were measured in plasma and cerebral cortex by radioimmunoassay. We found genetic variation in basal DOC levels measured following saline administration in both plasma and cerebral cortex. Plasma DOC levels across 35 BXD strains range between 2.8 and 12.1 ng/ml, resulting in a 4.3-fold variation. Cerebral cortex DOC levels across 24 strains range between 2.5 and 12.2 ng/g, resulting in a 4.9-fold variation. A correlation between plasma vs. cerebral cortical basal levels across these strains was observed (Spearman r=0.77, p<0.0001, n=26). Suggestive quantitative trait loci (QTLs) for basal DOC levels were found on chromosomes 4 and 17. The dexamethasone-induced changes in DOC levels showed a 3.4-fold variation in plasma across 35 BXD strains and a 4.2-fold variation in cerebral cortex across 24 strains. A correlation between dexamethasone-induced changes in plasma vs. cerebral cortex DOC levels was observed (Spearman r=0.66, p=0.0002, n=26). Suggestive QTLs for the dexamethasone-induced changes in plasma and cerebral cortical DOC levels were found on chromosomes 1, 2, 3, 7 and 13. Finally, variations in basal and dexamethasone-induced changes in plasma and cerebral cortical DOC levels were correlated with several ethanol and anxiety behavioral phenotypes using public data sets on GeneNetwork.org. The results suggest that DOC and dexamethasone effects on DOC levels may represent neuroendocrine biomarkers for alcohol and/or anxiety phenotypes in mice that could potentially persist across different species.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
