Plasma 5α–androstane–3α,17βdiol, an endogenous steroid that positively modulates GABAA receptor function, and anxiety: a study in menopausal women

Barbaccia, Maria Luisa; Lello, Stefano; Sidiropoulou, Tatiana; Cocco, Tiziana; Sorge, R; Cocchiarale, A; Piermarini, V; Sabato, Alessandro; Trabucchi, Marco; Romaninï, Carlo

doi:10.1016/s0306-4530(00)00017-2

Cited by 42 publications

(21 citation statements)

References 48 publications

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“…5. Since GABA-active neurosteroids play an important role in the pathogenesis of anxiety and depression [Strohle et al, 1999;Guidotti et al, 2001;Reddy, 2003], it is possible to expect that novel GABAergic steroid agents will be a useful tool in the treatment of steroid-dependent disorders including premenstrual and menopausal syndromes [Barbaccia et al, 2000;Sundstrom et al, 1997;SundstromPoromaa et al, 2003] characterized by increased anxiety and depression. In addition, steroids may play a unique modulatory role in tuning sensitivity of GABAergic receptors to GABA and other GABAactive substances [Turner et al, 1989;Olsen et al, 1991; also see Olsen and Sapp, 1995, for review].…”

Section: Resultsmentioning

confidence: 99%

Role of GABA in anxiety and depression

2007

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This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.

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Section: Resultsmentioning

confidence: 99%

Role of GABA in anxiety and depression

2007

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“…These data suggest that neuroactive steroid could have a role in preventing the expression of anxiety. 33 Increased levels of progesterone, AP, tetrahydrodeoxycorticosterone and pregnanolone were found in female patients with panic disorder, suggesting that neuroactive steroids with anxiolytic activity increase as a homeostatic mechanism to counteract the underlying hyperactivity of the HPA axis. 34 There is a common belief that OW children are unhappy with their weight and experience more psychosocial distress, particularly depressive symptoms.…”

Section: Discussionmentioning

confidence: 99%

High basal serum allopregnanolone levels in overweight girls

et al. 2006

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Objective: Several studies demonstrated that obese subjects have a hyperactive hypothalamic-pituitary-adrenal axis and that sex steroid hormones have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Allopregnanolone (3a-hydroxy-5a-pregn-20-one; AP) is a circulating neuroactive steroid hormone involved in the modulation of behavioral functions, stress and neuroendocrine axis. The aim of our study was to evaluate basal serum AP levels in obese children. Subjects and measurements: We studied 27 normal weight (NW) and 23 overweight (OW) girls. Gonadotropins and steroid hormones were assessed in all patients. Results: Basal AP concentrations in OW girls were significantly higher than in NW controls (P ¼ 0.013). There was no difference found between the other gonadal and adrenal hormones. Considering the pubertal stage, we demonstrated that obese pubertal girls presented higher AP concentrations than prepubertal and pubertal NW ones (P ¼ 0.020), and higher dehydroepiandrosterone sulfate (DHEAS) levels with respect to prepubertal obese girls, and prepubertal and pubertal NW patients (P ¼ 0.025). AP and DHEAS were significantly directly related to weight (r ¼ 0.31 and r ¼ 0.54, respectively) and body mass index (r ¼ 0.29 and r ¼ 0.34, respectively). In pubertal OW girls, a significant positive correlation between AP and DHEAS (r ¼ 0.60), A (r ¼ 0.72) and luteinizing hormone (r ¼ 0.64) levels was demonstrated. Conclusion: The present study demonstrates that AP is hypersecreted in children and adolescent with OW involving DHEAS concentrations, too. Our data suggest a possible role of AP in the regulation of neuroendocrine axis related to obesity. We can also speculate that in OW girls, who could manifest emotional and behavioral problems, a part of higher levels of this neuroactive steroid might act as g-aminobutyric acid agonist producing anxiolytic-sedative effects.

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“…4) 3a,5a-Adiol is structurally similar to AP and is also a potent positive modulator of GABA A receptors with anxiolytic and anticonvulsant effects. 4,5) The anticonvulsant profile of 3a,5a-Adiol is highly consistent with AP, which have been proven by several animal experiments. 4) However, it is not currently known if Fluox influences the brain and serum levels of 3a,5a-Adiol.…”

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confidence: 52%

Studies on Neurosteroids XXVI. Fluoxetine-Evoked Changes in Rat Brain and Serum Levels of Neuroactive Androgen, 5.ALPHA.-Androstane-3.ALPHA.,17.BETA.-diol

Higashi

Nagura

Shimada

et al. 2009

Biological & Pharmaceutical Bulletin

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Neuroactive steroids affect neurotransmission by action at the membrane ion-gated receptors and at other neurotransmitter receptors. 3a-Hydroxy-5a-pregnan-20-one (allopregnanolone, AP, Fig. 1), a representative neuroactive steroid, binds to the g-aminobutyric acid type A (GABA A ) receptors with a high affinity and positively modulates the action of GABA at these receptors, and hence elicits marked antidepressant, anxiolytic and anticonvulsant effects. 1) AP is synthesized from progesterone (PROG) via 5a-dihydroprogesterone (5a-DHP) by sequential reduction mediated by 5a-reductase and 3a-hydroxysteroid dehydrogenase (3a-HSD).Recent evidence also suggests that AP may be relevant to antidepressant drug action and depression pathophysiology.2,3) Fluoxetine (Fluox) is a typical selective serotonin (5-HT) reuptake inhibitor (SSRI) and is clinically used for the treatment of depression. However, Pinna et al. demonstrated that Fluox increases the brain AP content and subsequent activation of GABA A receptors at doses that are inactive toward the 5-HT reuptake, but does effectively treat depression. 3)Based on this result, Pinna et al. further stated that the term "SSRI" may be misleading in describing the pharmacological profile of Fluox and suggested the term "selective brain steroidogenic stimulant (SBSS)" as a better descriptor.3) Furthermore, rodent studies examining the Fluox-induced elevation in the brain AP level demonstrated that the effect is present to the same extent in both adrenalectomized and intact animals, suggesting that the Fluox-induced elevation in the brain AP level is due to de novo AP biosynthesis in the brain.2) 5a-Androstane-3a,17b-diol (3a,5a-Adiol, Fig. 1) is the best-characterized neuroactive androgen and derived from testosterone (T) by the action of 5a-reductase and 3a-HSD. 4) 3a,5a-Adiol is structurally similar to AP and is also a potent positive modulator of GABA A receptors with anxiolytic and anticonvulsant effects. 4,5) The anticonvulsant profile of 3a,5a-Adiol is highly consistent with AP, which have been proven by several animal experiments. 4) However, it is not currently known if Fluox influences the brain and serum levels of 3a,5a-Adiol. Examination of this point can be useful in evaluating the exact mechanisms of action of Fluox. Based on this background information, the objectives of this study are to determine the Fluox-evoked changes in the brain and serum 3a,5a-Adiol levels and to compare the level changes of 3a,5a-Adiol to those of AP. MATERIALS AND METHODS Materials and ReagentsAll the steroids including the deuterium-labeled internal standards (ISs) used in this study are those used in the previous studies.6-8) Each steroid was dissolved in and diluted with ethanol to prepare the standard solutions. Fluox was obtained from Wako Pure Chemical It is well known that fluoxetine (Fluox), a selective serotonin reuptake inhibitor, increases the brain content of allopregnanolone (AP), a potent neuroactive steroid that positively modulates the action of g g-aminobutyric acid (G...

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Plasma 5α–androstane–3α,17βdiol, an endogenous steroid that positively modulates GABAA receptor function, and anxiety: a study in menopausal women

Cited by 42 publications

References 48 publications

Role of GABA in anxiety and depression

Role of GABA in anxiety and depression

High basal serum allopregnanolone levels in overweight girls

Studies on Neurosteroids XXVI. Fluoxetine-Evoked Changes in Rat Brain and Serum Levels of Neuroactive Androgen, 5.ALPHA.-Androstane-3.ALPHA.,17.BETA.-diol

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