Abstract
BackgroundDeoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3α,5α)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence.Methodology/Principal FindingsTo systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)×DBA/2J (D2) (BXD) mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of ∼0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of ∼0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories.Conclusions/SignificanceBoth basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.
Highlights
IntroductionDeoxycorticosterone (DOC) is an endogenous neurosteroid present in the brain as well as in the peripheral circulation
Deoxycorticosterone (DOC) is an endogenous neurosteroid present in the brain as well as in the peripheral circulation. It is synthesized from progesterone, mainly in the adrenal zona fasciculata and it is precursor of both the glucocorticoid corticosterone and the GABAergic neuroactive steroid (3a,5a)3,21-dihydroxypregnan-20-one
We have found that dexamethasone suppression of plasma DOC levels predicted subsequent voluntary alcohol consumption in ethanol-naıve cynomolgus monkeys [9]
Summary
Deoxycorticosterone (DOC) is an endogenous neurosteroid present in the brain as well as in the peripheral circulation It is synthesized from progesterone, mainly in the adrenal zona fasciculata and it is precursor of both the glucocorticoid corticosterone and the GABAergic neuroactive steroid (3a,5a)3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC). These steroids are all elevated following acute stress [1] or ethanol administration in rats, and their elevation is blunted in ethanol dependence [2,3,4]. Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3a,5a)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence
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