Inhibition by <i>α</i>‐Tetrahydrodeoxycorticosterone (THDOC) of Pre‐Sympathetic Parvocellular Neurones in the Paraventricular Nucleus of Rat Hypothalamus

Womack, Matthew; Pyner, Susan; Barrett‐Jolley, Richard

doi:10.1038/sj.bjp.0706911

Cited by 17 publications

(15 citation statements)

References 45 publications

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“…Past studies showed that THDOC positively modulates GABA A receptor currents in parvocellular neurons of the paraventricular nucleus of the hypothalamus (Womack et al 2006). Fluctuation in neurosteroid concentration is associated with altered neural expression of GABA A receptor subtypes (Concas et al 1998) and GABA release (for a review, see Helms et al 2012c).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

2014

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“…5␣-Reductase and 3␣-HSD also metabolize 11-deoxycorticosterone (DOC), from the adrenal cortex, to 3␣,5␣-tetrahydrodeoxycorticosterone (TH-DOC), a neurosteroid acting like allopregnanolone (Womack et al, 2006). DOC secretion is increased by acute stress (Reddy and Rogawski, 2002a), but finasteride actions via decreased TH-DOC formation in the current study are unlikely because corticosterone levels in pregnant rats were no greater than in virgins.…”

Section: Allopregnanolone-synthesizing Enzymesmentioning

confidence: 93%

Central Opioid Inhibition of Neuroendocrine Stress Responses in Pregnancy in the Rat Is Induced by the Neurosteroid Allopregnanolone

Brunton¹,

McKay²,

et al. 2009

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The hypothalamus-pituitary-adrenal (HPA) axis is the major neuroendocrine stress response system. Corticotropin-releasing hormone (CRH) neurons in the parvocellular paraventricular nucleus (pPVN) play a key role in coordinating responses of this system to stressors. The cytokine interleukin-1␤ (IL-1␤), mimicking infection, robustly activates these CRH neurons via a noradrenergic input arising from the nucleus tractus solitarii (NTS). In late pregnancy, HPA axis responses to stressors, including IL-1␤, are attenuated by a central opioid mechanism that auto-inhibits noradrenaline release in the PVN. Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in HPA responsiveness to IL-1␤ in pregnancy. In late pregnancy, inhibition of 5␣-reductase (an allopregnanolone-synthesizing enzyme) with finasteride restored HPA axis responses (rapidly increased pPVN CRH mRNA expression, ACTH, and corticosterone secretion) to IL-1␤. Conversely, allopregnanolone reduced HPA responses in virgin rats. In late pregnancy, activity of the allopregnanolone-synthesizing enzymes (5␣-reductase and 3␣-hydroxysteroid dehydrogenase) was increased in the hypothalamus as was mRNA expression in the NTS and PVN. Naloxone, an opioid antagonist, restores HPA axis responses to IL-1␤ in pregnancy but had no additional effect after finasteride, indicating a causal connection between allopregnanolone and the endogenous opioid mechanism. Indeed, allopregnanolone induced opioid inhibition over HPA responses to IL-1␤ in virgin rats. Furthermore, in virgin rats, allopregnanolone treatment increased, whereas in pregnant rats finasteride decreased proenkephalin-A mRNA expression in the NTS. Thus, in pregnancy, allopregnanolone induces opioid inhibition over HPA axis responses to immune challenge. This novel opioid-mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy.

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“…In common, the output of spinally projecting parvocellular neurons is similarly reduced by low concentrations of 5α3α-THDOC (Womack et al, 2006). Neuroendocrine parvocellular neurons are known to activate the HPA axis through the release of CRH (Vale et al, 1981) and i.c.v.…”

Section: Physiological and Pathophysiological Role Of Neurosteroids: mentioning

confidence: 99%

Neurosteroids and GABAA Receptor Interactions: A Focus on Stress

Gunn¹,

Brown²,

Lambert³

et al. 2011

Front. Neurosci.

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Since the pioneering discovery of the rapid CNS depressant actions of steroids by the “father of stress,” Hans Seyle 70 years ago, brain-derived “neurosteroids” have emerged as powerful endogenous modulators of neuronal excitability. The majority of the intervening research has focused on a class of naturally occurring steroids that are metabolites of progesterone and deoxycorticosterone, which act in a non-genomic manner to selectively augment signals mediated by the main inhibitory receptor in the CNS, the GABAA receptor. Abnormal levels of such neurosteroids associate with a variety of neurological and psychiatric disorders, suggesting that they serve important physiological and pathophysiological roles. A compelling case can be made to implicate neurosteroids in stress-related disturbances. Here we will critically appraise how brain-derived neurosteroids may impact on the stress response to acute and chronic challenges, both pre- and postnatally through to adulthood. The pathological implications of such actions in the development of psychiatric disturbances will be discussed, with an emphasis on the therapeutic potential of neurosteroids for the treatment of stress-associated disorders.

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Inhibition by α‐Tetrahydrodeoxycorticosterone (THDOC) of Pre‐Sympathetic Parvocellular Neurones in the Paraventricular Nucleus of Rat Hypothalamus

Cited by 17 publications

References 45 publications

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

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

Central Opioid Inhibition of Neuroendocrine Stress Responses in Pregnancy in the Rat Is Induced by the Neurosteroid Allopregnanolone

Neurosteroids and GABAA Receptor Interactions: A Focus on Stress

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