Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor

Bitran, Daniel; Hilvers, Robert J.; Kellogg, Carol K.

doi:10.1016/0006-8993(91)90761-j

Cited by 428 publications

(201 citation statements)

References 24 publications

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“…This latter action may be similar to that of progesterone, which increases amygdala reactivity in healthy young women (van Wingen et al, 2007). Animal studies have demonstrated that the acute effects of progesterone are mediated by its neuroactive metabolite allopregnanolone that also exerts its action by binding to the GABA A receptor (Bitran et al, 1991(Bitran et al, , 1995, suggesting a common pathway by which neuroactive steroids could modulate amygdala function.…”

Section: Discussionmentioning

confidence: 91%

Testosterone Increases Amygdala Reactivity in Middle-Aged Women to a Young Adulthood Level

Wingen

Zylicz

Pieters

et al. 2008

Neuropsychopharmacol

122

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Testosterone modulates mood and sexual function in women. However, androgen levels decline with age, which may relate to the ageassociated change in sexual functioning and the prevalence of mood and anxiety disorders. These effects of testosterone are potentially mediated by the amygdala. In the present study, we investigated whether the age-related decline in androgen levels is associated with reduced amygdala activity, and whether exogenous testosterone can restore amygdala activity. Healthy young and middle-aged women participated during the early follicular phase of the menstrual cycle, and amygdala responses to biologically salient stimuli were measured with functional magnetic resonance imaging (fMRI). Androgen levels were lower in middle-aged than young women, which was associated with decreased amygdala reactivity. Endogenous testosterone levels correlated positively with amygdala reactivity across the young and middle-aged women. The middle-aged women received a single nasal dose of testosterone in a double-blind, placebocontrolled, crossover manner, which rapidly increased amygdala reactivity to a level comparable to the young women. The enhanced testosterone levels correlated positively with superior frontal cortex responses and negatively with orbitofrontal cortex responses across individuals, which may reflect testosterone-induced changes in amygdala regulation. These results show that testosterone modulates amygdala reactivity in women, and suggest that the age-related decline in androgen levels contribute to the decrease in amygdala reactivity.

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Section: Discussionmentioning

confidence: 91%

Testosterone Increases Amygdala Reactivity in Middle-Aged Women to a Young Adulthood Level

Wingen

Zylicz

Pieters

et al. 2008

Neuropsychopharmacol

122

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“…This finding is consistent with an earlier parallel study that was conducted in male C57BL/6 and DBA/2 mice (Finn et al, 2000). The ability of ALLO pre-treatment to decrease plasma corticosterone levels may be due to the anxiolytic effect of this steroid (e.g., Akwa et al, 1999;Bitran et al, 1991Bitran et al, , 1999Finn et al, 1997) and/or the ability of ALLO to decrease the stress-induced increase in HPA axis activation (Patchev et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Beckley¹,

Fretwell²,

Tanchuck³

et al. 2008

Neuropharmacology

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SUMMARYThe GABAergic neurosteroid allopregnanolone (ALLO) has been repeatedly shown to have an increased anticonvulsant effect during ethanol withdrawal in rats and in C57BL/6J mice. In contrast, the seizure prone DBA/2J inbred strain and the Withdrawal Seizure-Prone (WSP) selected line exhibited decreased sensitivity to ALLO's anticonvulsant effect during ethanol withdrawal, with no change in sensitivity in the Withdrawal Seizure-Resistant (WSR) line. To date, only male mice have been tested. Thus, the present study examined ALLO sensitivity during ethanol withdrawal in female WSP and WSR mice, since females display less severe physical symptoms of withdrawal and have higher circulating ALLO levels than males. Female WSP and WSR mice were exposed to ethanol vapor or air for 72 hr. During peak ethanol withdrawal, separate groups of mice were injected with vehicle or ALLO (0, 3.2, 10, or 17 mg/kg, ip) prior to the timed tail vein infusion of pentylenetetrazol (PTZ). ALLO injection significantly increased the threshold dose for onset to PTZ-induced convulsions, indicating an anticonvulsant effect, in female WSP and WSR mice. During ethanol withdrawal, sensitivity to ALLO's anticonvulsant effect was slightly increased in female WSR mice but was significantly decreased in female WSP mice. This line difference in sensitivity to ALLO during ethanol withdrawal in female mice was similar to that in the male mice. Notably, all seizure prone genotypes tested to date displayed tolerance to the anticonvulsant effect of ALLO during ethanol withdrawal, suggesting that decreased sensitivity of GABA A receptors to ALLO may contribute to the increased ethanol withdrawal phenotype.

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“…Neuroactive steroids have been shown to influence the brain and in particular they can influence neurotransmitters involved in anxiety. Evidence that AP has anxiolytic properties in different animal models 31,32 has suggested that alterations of neuroactive steroid secretion might be implicated in the pathogenetic mechanisms of anxiety disorders in humans. There are few data on neuroactive steroid secretion in anxiety disorders.…”

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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Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor

Cited by 428 publications

References 24 publications

Testosterone Increases Amygdala Reactivity in Middle-Aged Women to a Young Adulthood Level

Testosterone Increases Amygdala Reactivity in Middle-Aged Women to a Young Adulthood Level

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

High basal serum allopregnanolone levels in overweight girls

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