Ethanol induction of steroidogenesis in rat adrenal and brain is dependent upon pituitary ACTH release and de novo adrenal StAR synthesis

Abstract

J. Neurochem. (2010) 112, 784–796. Abstract The mechanisms of ethanol actions that produce its behavioral sequelae involve the synthesis of potent GABAergic neuroactive steroids, specifically the GABAergic metabolites of progesterone, (3α,5α)‐3‐hydroxypregnan‐20‐one (3α,5α‐THP), and deoxycorticosterone, (3α,5α)‐3,21‐dihydroxypregnan‐20‐one. We investigated the mechanisms that underlie the effect of ethanol on adrenal steroidogenesis. We found that ethanol effects on plasma pregnenolone, progesterone, 3α,5α‐THP and cortical 3α,5α‐THP are highly correlated, exhibit a threshold of 1.5 g/kg, but show no dose dependence. Ethanol increases plasma adrenocorticotropic hormone (ACTH), adrenal steroidogenic acute regulatory protein (StAR), and adrenal StAR phosphorylation, but does not alter levels of other adrenal cholesterol transporters. The inhibition of ACTH release, de novo adrenal StAR synthesis or cytochrome P450 side chain cleavage activity prevents ethanol‐induced increases in GABAergic steroids in plasma and brain. ACTH release and de novo StAR synthesis are independently regulated following ethanol administration and both are necessary, but not sufficient, for ethanol‐induced elevation of plasma and brain neuroactive steroids. As GABAergic steroids contribute to ethanol actions and ethanol sensitivity, the mechanisms of this effect of ethanol may be important factors that contribute to the behavioral actions of ethanol and risk for alcohol abuse disorders.

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

“…Therefore, ethanol-induced changes in cellular 3a,5a-THP are bidirectional, brain region/cell population-specific, and occur locally in the rat brain. The current IHC results and previous reports using RIA or GC-MS suggest ethanol-induced elevations of 3a,5a-THP in the cerebral cortex are dependent on the adrenal or pituitary glands (Boyd et al, 2010). It is not clear why there is a dependence on the HPA axis to observe cerebral cortical elevations of 3a,5a-THP; however, one possibility is a lack of precursor in the cortex.…”

“…Indeed, it has been shown that administration of 5a-dihydroprogesterone (5a-DHP), the immediate precursor of 3a,5a-THP, restores ethanol-induced increases of 3a,5a-THP in the cerebral cortex (Khisti et al, 2003). It has also been shown that de novo adrenal synthesis of the cholesterol transporter StAR is necessary for ethanol-induced increases of 3a,5a-THP in the cerebral cortex (Boyd et al, 2010). StAR transports cholesterol to the inner mitochondrial membrane where it is converted to pregnenolone by cytochrome P450 side chain cleavage (P450scc).…”

“…Therefore, de novo StAR synthesis in the adrenals may be necessary to provide precursor and/or 3a,5a-THP to the cerebral cortex following ethanol administration. Previous work has shown that acute ethanol increases StAR and P450scc mRNA in the rat frontal cortex (Kim et al, 2003); however, no increase in the StAR protein was found in whole cortex and TSPO protein levels were reduced (Boyd et al, 2010). The synthesis of 3a,5a-THP is accomplished by 5a-R converting progesterone to 5a-DHP, which 3a-hydroxysteroid dehydrogenase (3a-HSD) then converts to 3a,5a-THP.…”

“…The presence of ethanol-induced local brain synthesis of 3a,5a-THP is controversial since there are conflicting data depending on the model system used. In vivo, studies suggest ethanol-induced elevations of 3a,5a-THP in the cerebral cortex are dependent on circulating steroids since adrenalectomy (ADX) and hypophysectomy prevent ethanol-induced increases in cerebral cortical 3a,5a-THP (Boyd et al, 2010;Khisti et al, 2003;O'Dell et al, 2004;Porcu et al, 2004). In vitro studies, however, suggest that ethanol produces local brain synthesis of 3a,5a-THP using the hippocampal tissue from intact (Sanna et al, 2004;Tokuda et al, 2011) and adrenalectomized/gonadectomized (Follesa et al, 2006) rats.…”

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

“…In particular, THDOC and THP (Fig. 3) have GABA A receptor-positive modulatory effects and produce inhibitory neurobehavioural effects, including anxiolytic, anticonvulsant and sedative actions (Biggio et al 2007, Morrow 2007, and may mediate some of the actions of ethanol (Biggio et al 2007, Boyd et al 2010, Kaufman et al 2010. THDOC and allopregnanolone also have actions on the hypothalamus pituitary-adrenal axis and thereby on the effects of stress (Girdler & Klatzkin 2007).…”