Hypothalamic–pituitary–adrenal axis and ethanol modulation of deoxycorticosterone levels in cynomolgus monkeys

Porcu, Patrizia; Grant, Kathleen A.; Green, Heather L.; Rogers, Laura S. M.; Morrow, A. Leslie

doi:10.1007/s00213-005-0132-2

Cited by 28 publications

(44 citation statements)

References 52 publications

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“…As described by Porcu et al (2006), training was conducted using positive reinforcement (fresh fruit) as the animal sat at the front of the cage and presented its leg through an opening (10 × 10 cm). Once comfortable, a dental pick was used to simulate a needle stick at the femoral vein.…”

Section: Methodsmentioning

confidence: 99%

“…After acute ethanol administration, the precursor to all steroid hormones, pregnenolone, was decreased in macaque monkeys (Porcu et al 2006) and increased in humans who were social drinkers (Pierucci-Lagha et al 2006). Likewise, following acute ethanol in cynomolgus monkeys or humans, the neuroactive steroid precursors progesterone and DOC, as well as the neuroactive metabolite 3α,5α-pregnanolone and the mineralocorticoid aldosterone are either not increased or are decreased (Porcu et al, 2006; 2010; Pierucci-Lagha et al 2006; Nieminen et al 1981). Lastly, ethanol challenge did not increase the neurosteroid DHEA in human males (Pierucci-Lagha et al 2006).…”

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confidence: 99%

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Adrenal steroid hormones and ethanol self-administration in male rhesus macaques

2014

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Rationale Hypothalamic-pituitary-adrenal (HPA) axis hormones have neuroactive metabolites with receptor activity similar to ethanol. Objectives The present study related HPA hormones in naïve monkeys to ethanol self-administration. Methods Morning plasma adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone (DOC), aldosterone and dehydroepiandrosterone-sulfate (DHEA-S) were measured longitudinally in male rhesus macaques (Macaca mulatta) induced to drink ethanol followed by access to ethanol (4% w/v, in water) and water 22 hours/day for 12 months. Results During ethanol access, DOC increased among non-heavy (average intake over 12 months ≤ 3.0 g/kg/day, n = 23) but not heavy drinkers (> 3.0 g/kg/day, n = 9), aldosterone was greater among heavy drinkers after 6 months. The ratio of DOC/aldosterone decreased only among heavy drinkers after 6 or12 months of ethanol self-administration. ACTH only correlated significantly with DHEA-S, the ratio of cortisol/DHEA-S and DOC after the onset of ethanol access, the former two just in heavy drinkers. Baseline hormones did not predict subsequent ethanol intake over 12 months, but baseline DOC correlated with average blood-ethanol concentrations (BEC), among all monkeys and heavy drinkers as a group. During ethanol access, aldosterone and DOC correlated and tended to correlate, respectively, with 12-month average ethanol intake. Conclusions Ethanol self-administration lowered ACTH and selectively altered its adrenocortical regulation. Mineralocorticoids may compensate for adrenocortical adaptation among heavy drinkers and balance fluid homeostasis. As DOC was uniquely predictive of future BEC) and not water intake, to the exclusion of aldosterone, GABAergic neuroactive metabolites of DOC may be risk factors for binge drinking to intoxication.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Adrenal steroid hormones and ethanol self-administration in male rhesus macaques

2014

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“…DOC is an endogenous neuroactive steroid, synthesized from progesterone mainly in the adrenal glands but also in the brain; it is the precursor of the GABAergic neuroactive steroid 3α,5α-THDOC and of the glucocorticoid corticosterone. DOC levels are elevated in rat brain and mouse plasma following acute ethanol administration (Khisti et al 2005; Porcu et al 2010), are regulated by hypothalamic and pituitary activation of the HPA axis in both cynomolgus monkeys and humans and this regulation is altered following ethanol dependence (Porcu et al 2006; Porcu et al 2008). Across the BXD mouse population we found significant genetic variation in basal DOC levels.…”

Section: Genetic Variation In Neuroactive Steroid Levels Across Bxd Rmentioning

confidence: 99%

Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies

Porcu

Morrow

2014

Psychopharmacology

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Rationale Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily GABAA receptors. Neuroactive steroids regulate many physiological processes including hypothalamic-pituitary-adrenal (HPA) axis function, ovarian cycle, pregnancy, aging, and reward. Moreover, alterations in neuroactive steroid synthesis are implicated in several neuropsychiatric disorders. Objectives This review will summarize the pharmacological properties and physiological regulation of neuroactive steroids, with a particular focus on divergent neuroactive steroid responses to stress and ethanol in rats, mice and humans. Results GABAergic neuroactive steroids exert a homeostatic regulation of the HPA axis in rats and humans, whereby the increase in neuroactive steroid levels following acute stress counteracts HPA axis hyperactivity and restores homeostasis. In contrast, in C57BL/6J mice, acute stress decreases neurosteroidogenesis and neuroactive steroids exert paradoxical excitatory effects upon the HPA axis. Rats, mice and humans also differ in the neuroactive steroid responses to ethanol. Genetic variation in neurosteroidogenesis may explain the different neuroactive steroid responses to stress or ethanol. Conclusions Rats and mouse strains show divergent effects of stress and ethanol on neuroactive steroids in both plasma and brain. The study of genetic variation in the various processes that determine neuroactive steroids levels as well as their effects on cell signaling may underlie these differences and may play a relevant role for the potential therapeutic benefits of neuroactive steroids.

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“…In humans, deoxycorticosterone plasma levels are increased following ACTH administration and decreased after dexamethasone administration (Brown and Strott, 1971;Tan and Mulrow, 1975;Kater et al, 1990), suggesting potential regulation by the hypothalamic-pituitary-adrenal (HPA) axis. In agreement, (Porcu et al 2006a) have shown that plasma deoxycorticosterone levels in cynomolgus monkeys are increased by naloxone and CRH challenges and decreased by dexamethasone challenge.…”

Section: Introductionmentioning

confidence: 54%

“…Deoxycorticosterone assay-Deoxycorticosterone levels were determined by RIAas previously described (Porcu et al, 2006a). Briefly, plasma samples (200 µl) were extracted twice with 2 ml ethyl acetate/hexane (3:2) 1000 cpm aliquot of [ 3 H]deoxycorticosterone (SpA = 50 Ci/mmol; American Radiolabeled Chemicals, Inc. Saint Louis, MO, USA) was added to each sample for recovery estimation.…”

Section: Dexamethasone Plus Cosyntropin Challengementioning

confidence: 99%

Differential hypothalamic–pituitary–adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects

Porcu

O'Buckley

Morrow

et al. 2008

Psychoneuroendocrinology

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SummaryEthanol and the neuroactive steroids have interactive neuropharmacological effects and chronic ethanol administration blunts the ethanol-induced increase in neuroactive steroid levels in rodent plasma and brain. Few studies have explored neuroactive steroid regulation in alcohol-dependent human subjects. In fact, the regulation of adrenal neuroactive steroids has not been well defined in healthy controls. We thus explored the regulation of two neuroactive steroids, pregnenolone sulfate (PREG-S) and deoxycorticosterone, by pharmacological challenges to the hypothalamic-pituitaryadrenal (HPA) axis in healthy controls and one-month abstinent alcohol-dependent patients with cooccurring nicotine dependence. Plasma levels of PREG-S and deoxycorticosterone were measured by radioimmunoassay in controls and alcohol-dependent patients after challenges of naloxone, ovine corticotrophin releasing hormone (oCRH), dexamethasone, cosyntropin, and cosyntropin following high-dose dexamethasone. In addition, basal diurnal measures of both hormones were obtained. PREG-S plasma levels in healthy controls were increased by cosyntropin challenge (with and without dexamethasone pretreatment) and decreased by dexamethasone challenge. However, PREG-S concentrations were not altered by naloxone or oCRH challenges, suggesting that PREG-S is not solely regulated by hypothalamic or pituitary stimulation. Deoxycorticosterone, in contrast, is regulated by HPA challenge stimulation in a manner similar to cortisol. Alcohol-dependent patients had a blunted PREG-S response to cosyntropin (with and without dexamethasone pretreatment). Furthermore, the time to peak deoxycorticosterone response following oCRH was delayed in alcoholdependent patients compared to controls. These results indicate that plasma PREG-S and deoxycorticosterone levels are differentially regulated by HPA axis modulation in human plasma. Further, alcohol-dependent patients show a blunted PREG-S response to adrenal stimulation and a delayed deoxycorticosterone response to oCRH challenge.

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Hypothalamic–pituitary–adrenal axis and ethanol modulation of deoxycorticosterone levels in cynomolgus monkeys

Abstract: These results suggest that DOC levels in monkeys are regulated by the HPA axis and may contribute to physiological responses following activation.

Cited by 28 publications

References 52 publications

Adrenal steroid hormones and ethanol self-administration in male rhesus macaques

Adrenal steroid hormones and ethanol self-administration in male rhesus macaques

Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies

Differential hypothalamic–pituitary–adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects

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