Failure of γ-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized–orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals

Porcu, Patrizia; Sogliano, Cristiana; Ibba, Cristina; Piredda, Massimo; Tocco, S.; Marra, Carla; Purdy, Robert H.; Biggio, Giovanni; Concas, Alessandra

doi:10.1016/j.brainres.2004.03.059

Cited by 23 publications

(20 citation statements)

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“…Ethanolinduced elevations of 3a,5a-THP in the mPFC appear to be dependent on the adrenals. This finding is consistent with studies using RIA to measure 3a,5a-THP in whole cerebral cortex (Khisti et al, 2003;Porcu et al, 2004) or GC-MS measuring 3a,5a-THP in the frontal cortex (O'Dell et al, 2004). Interestingly, ethanol-induced elevations of 3a,5a-THP in the pyramidal cell layer of the hippocampus, and polymorphic cell layer of the DG, BNST, and PVN were observed following ADX.…”

Section: Discussionsupporting

confidence: 89%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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The neuroactive steroid (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) is a positive modulator of GABA A receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic-pituitary-adrenal axis and elevates 3a,5a-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3a,5a-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3a,5a-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3a,5a-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3a,5a-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3a,5a-THP following ADX. In subcortical regions, 3a,5a-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3a,5a-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3a,5a-THP levels in several subcortical regions; however, the adrenal glands contribute to 3a,5a-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3a,5a-THP induction by ethanol is not due to a lack of colocalization of 3a,5a-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO).

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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“…This finding is consistent with the potent neuroendocrine stimulatory effects elicited by nicotine and morphine in rodents on the release of corticotropin-releasing factor (CRF) in the hypothalamus, which, in turn, increases the plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (Buckingham 1982;Matta et al 1998). The increases in the cerebrocortical levels of neurosteroids induced either by stressful conditions (Barbaccia et al 1997) or by administration of psychoactive drugs such as alcohol, caffeine, and γ-hydroxybutyric acid (Concas et al 2000;Khisti et al 2002;Porcu et al 2004) are also not evident in Adx-Orx animals. Therefore, our results further support the notion that the HPA axis plays an important role in determining the peripheral and central concentrations of neurosteroids elicited by drugs of abuse.…”

Section: Discussionsupporting

confidence: 75%

“…However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear. The observation that morphine and nicotine share with alcohol, caffeine, and γ-hydroxybutyrate (Concas et al 2000;VanDoren et al 2000;Barbaccia et al 2002;Porcu et al 2004) the ability to increase the brain concentrations of neurosteroids suggests that these steroids may play a role in neurochemical mechanisms that underlie drug addiction.…”

Section: Discussionmentioning

confidence: 98%

Neurosteroids in nicotine and morphine dependence

et al. 2005

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Changes in neurosteroid concentrations mediated by activation of the HPA axis may both contribute to the early acquisition phase of nicotine or morphine addiction and serve to counteract the anxiety-like behavior associated with nicotine or morphine withdrawal. However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear.

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“…The ethanol-induced increase in plasma neuroactive steroids is mediated by the HPA axis, since it is no longer observed in hypophysectomized and adrenalectomized Sprague-Dawley (Boyd et al 2010; Khisti et al 2003; Porcu et al 2004) or Wistar (O'Dell et al 2004) rats. However, studies of ethanol effects using immunohistochemistry reveal that ethanol-induced elevations of 3α,5α-THP are independent of adrenal activation in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus of Wistar rats.…”

Section: Gabaergic Neuroactive Steroids and Ethanol Interactionsmentioning

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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Failure of γ-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized–orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals

Cited by 23 publications

References 46 publications

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

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

Neurosteroids in nicotine and morphine dependence

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

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