GABAergic neuroactive steroids contribute to ethanol actions and regulate stress homeostasis in the central nervous system. Systemic ethanol administration increases plasma and cerebral cortical levels of deoxycorticosterone (DOC) in rodents. Furthermore, dexamethasone suppression of plasma DOC is predictive of subsequent voluntary alcohol consumption in ethanol-na?¨ve cynomolgus monkeys. That is, ethanol-na?¨ve monkeys that are insensitive to dexamethasone drink the most alcohol in a two bottle self-administration paradigm. In addition, dexamethasone suppression of plasma and cerebral cortex DOC levels is blunted in C57BL/6J compared to DBA/2J mice, and may correspond to higher ethanol intake in C57BL/6J mice. DOC levels and DOC sensitivity to dexamethasone were tested across the BXD recombinant inbred (RI) mice in order 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 8:00 am and were sacrificed 6 hours later. DOC levels were measured in plasma and cerebral cortex by radioimmunoassay. Basal cerebral cortical DOC levels across 42 BXD strains and the parental strains range between 1.4 and 12.2 ng/g, resulting in a 8.7-fold genetic variation [F(43,246)=4.33, p < .0001]. Basal plasma DOC levels across 47 BXD strains and the parental strains range between 2.8 and 12.1 ng/ml resulting in a 4.3-fold genetic variation [F(48,282)=3.69, p < .0001]. Quantitative trait loci (QTLs) for basal DOC levels were identified on chromosomes 4 and 14, respectively in cerebral cortex and plasma. Further, basal DOC levels were correlated with several behavioral measures of alcohol sensitivity across the BXD mice. The dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma. DOC sensitivity to dexamethasone also correlated with some behavioral measures of alcohol sensitivity across the BXD mice. In summary, this study identified two significant QTLs, associated with basal cerebral cortical and plasma DOC levels across the BXD mice. Furthermore, basal DOC levels were positively correlated with ethanol sensitivity, suggesting that the neuroactive steroid DOC may be a putative biomarker for alcohol responses. Supported by INIA-NIAAA AA013614 (PP), AA016672 and AA010564 (ALM), AA016662 (MFM, EJC), AA13499 and AA017590 (RWW).
Identification of QTLs for deoxycorticosterone levels across the BXD RI mice: A putative neuroactive steroid biomarker for alcohol phenotypes
Porcu P;
2010
Abstract
GABAergic neuroactive steroids contribute to ethanol actions and regulate stress homeostasis in the central nervous system. Systemic ethanol administration increases plasma and cerebral cortical levels of deoxycorticosterone (DOC) in rodents. Furthermore, dexamethasone suppression of plasma DOC is predictive of subsequent voluntary alcohol consumption in ethanol-na?¨ve cynomolgus monkeys. That is, ethanol-na?¨ve monkeys that are insensitive to dexamethasone drink the most alcohol in a two bottle self-administration paradigm. In addition, dexamethasone suppression of plasma and cerebral cortex DOC levels is blunted in C57BL/6J compared to DBA/2J mice, and may correspond to higher ethanol intake in C57BL/6J mice. DOC levels and DOC sensitivity to dexamethasone were tested across the BXD recombinant inbred (RI) mice in order 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 8:00 am and were sacrificed 6 hours later. DOC levels were measured in plasma and cerebral cortex by radioimmunoassay. Basal cerebral cortical DOC levels across 42 BXD strains and the parental strains range between 1.4 and 12.2 ng/g, resulting in a 8.7-fold genetic variation [F(43,246)=4.33, p < .0001]. Basal plasma DOC levels across 47 BXD strains and the parental strains range between 2.8 and 12.1 ng/ml resulting in a 4.3-fold genetic variation [F(48,282)=3.69, p < .0001]. Quantitative trait loci (QTLs) for basal DOC levels were identified on chromosomes 4 and 14, respectively in cerebral cortex and plasma. Further, basal DOC levels were correlated with several behavioral measures of alcohol sensitivity across the BXD mice. The dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma. DOC sensitivity to dexamethasone also correlated with some behavioral measures of alcohol sensitivity across the BXD mice. In summary, this study identified two significant QTLs, associated with basal cerebral cortical and plasma DOC levels across the BXD mice. Furthermore, basal DOC levels were positively correlated with ethanol sensitivity, suggesting that the neuroactive steroid DOC may be a putative biomarker for alcohol responses. Supported by INIA-NIAAA AA013614 (PP), AA016672 and AA010564 (ALM), AA016662 (MFM, EJC), AA13499 and AA017590 (RWW).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
