Sex‐dependent changes in neuroactive steroid concentrations in the rat brain following acute swim stress

Abstract

Sex differences in hypothalamic‐pituitary‐adrenal (HPA) axis activity are well established in rodents. In addition to glucocorticoids, stress also stimulates the secretion of progesterone and deoxycorticosterone (DOC) from the adrenal gland. Neuroactive steroid metabolites of these precursors can modulate HPA axis function; however, it is not known whether levels of these steroids differ between male and females following stress. In the present study, we aimed to establish whether neuroactive steroid concentrations in the brain display sex‐ and/or region‐specific differences under basal conditions and following exposure to acute stress. Brains were collected from male and female rats killed under nonstress conditions or following exposure to forced swimming. Liquid chromatography‐mass spectrometry was used to quantify eight steroids: corticosterone, DOC, dihydrodeoxycorticosterone (DHDOC), pregnenolone, progesterone, dihydroprogesterone (DHP), allopregnanolone and testosterone in plasma, and in five brain regions (frontal cortex, hypothalamus, hippocampus, amygdala and brainstem). Corticosterone, DOC and progesterone concentrations were significantly greater in the plasma and brain of both sexes following stress; however, the responses in plasma were greater in females compared to males. This sex difference was also observed in the majority of brain regions for DOC and progesterone but not for corticosterone. Despite observing no stress‐induced changes in circulating concentrations of pregnenolone, DHDOC or DHP, concentrations were significantly greater in the brain and this effect was more pronounced in females than males. Basal plasma and brain concentrations of allopregnanolone were significantly higher in females; moreover, stress had a greater impact on central allopregnanolone concentrations in females. Stress had no effect on circulating or brain concentrations of testosterone in males. These data indicate the existence of sex and regional differences in the generation of neuroactive steroids in the brain following acute stress, especially for the 5α‐reduced steroids, and further suggest a sex‐specific expression of steroidogenic enzymes in the brain. Thus, differential neurosteroidogenesis may contribute to sex differences in HPA axis responses to stress.

Effects of prenatal stress on neuroactive steroid responses to acute stress in adult male and female rats

“…Several steroids are rapidly produced as a physiological response to acute stress, where they act as allostatic mediators to allow the body to adapt and cope with the stressor 1 . As well as the production of glucocorticoids (ie, cortisol in humans, corticosterone in rats and mice) following activation of the hypothalamic‐pituitary‐adrenal (HPA) axis, other steroids are also produced, such as deoxycorticosterone (DOC), progesterone and their metabolites, with elevated levels detected in both the periphery and in the brain following acute stress 2‐4 . Steroids that exert rapid non‐genomic effects in the brain are collectively known as neuroactive steroids, 5 and they can originate from peripheral endocrine organs or are produced de novo via the action of steroidogenic enzymes such as 5α‐reductase and 3α‐hydroxysteroid dehydrogenase (3α‐HSD) expressed within the brain 6,7 .…”

Serum Neurosteroid Levels Are Associated With Cortical Thickness in Individuals Diagnosed With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury

“…99,100 Moreover, a recent study in mice showed that the stress-induced upregulation of ALLO and PREGN measured in the brain is higher in female mice. 101 Sex ratio was unequal across the 4 study groups. As women are known to have a greater range of ALLO levels due to elevated ALLO levels in the luteal phase of the menstrual cycle, the group difference between the PTSD + mTBI group and controls may have been in part driven by the higher percentage of women in the control group.…”

Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO2 inhalation in a female rat model of panic disorder

“…The sympathetic system regulates ovarian E 2 secretion 47 , and ovarian aromatase expression peaks during proestrus 48 . Since plasma E 2 closely reflects brain levels 49 , such impairment in E 2 signalling within the brain of NMS females is likely. The inability of NMS females to augment E 2 in response to CO 2 during proestrus suggests that NMS reduced E 2 synthesis capacity and thus compromise the response to an acute challenge.…”