Abstract
Acute swim stress results in the robust production of several neuroactive steroids, which act as mediators of the stress response. These steroids include glucocorticoids, and positive GABAA receptor modulatory steroids such as allopregnanolone and tetrahydrocorticosterone (THDOC), which potentiate inhibitory GABA signalling, thereby playing a role in the negative control of the hypothalamic‐pituitary‐adrenal (HPA) axis. Prenatally stressed (PNS) offspring exhibit increased vulnerability to stress‐related disorders and frequently display exaggerated HPA axis responses to stressors during adulthood, which may be a result of reduced neuroactive steroid production and consequently inhibitory signalling. Here, we investigated whether exposure of rats to prenatal social stress from gestational day 16‐20 altered neuroactive steroid production under non‐stress conditions and in response to an acute stressor (swim stress) in adulthood. Using liquid chromatography‐mass spectrometry, nine neuroactive steroids were quantified (corticosterone, deoxycorticosterone [DOC], dihydrodeoxycorticosterone, THDOC, progesterone, dihydroprogesterone, allopregnanolone, pregnenolone, testosterone) in plasma and in five brain regions (frontal cortex, hypothalamus, amygdala, hippocampus, brainstem) of male and female control and PNS rats. There was no difference in the neuroactive steroid profile between control and PNS rats under basal conditions. The increase in circulating corticosterone induced by acute swim stress was similar in control and PNS offspring. However, greater stress‐induced corticosterone and DOC concentrations were observed in the brainstem of male PNS offspring, whereas DOC concentrations were lower in the hippocampus of PNS females compared to controls, following acute stress. Although PNS rats did not show deficits in allopregnanolone responses to acute stress, there were modest deficits in the production of THDOC in the brainstem, amygdala, and frontal cortex of PNS males and in the frontal cortex of PNS females. The data suggest that neuroactive steroid modulation of GABAergic signalling following stress exposure may be affected in a sex‐ and region‐specific manner in PNS offspring.
Highlights
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]
Given allopregnanolone and THDOC potentiate the inhibitory effects of GABA on corticotropin-releasing hormone (CRH) neurones to decrease activity of the HPA axis,[14,16,31] we hypothesised that the concentrations of these 3α,5α-reduced GABAA modulatory neuroactive steroids would be lower in the brains of prenatally stressed (PNS) offspring compared to control offspring following acute stress
The present study aimed to determine whether the steroidal profile of prenatally stressed offspring differed from that of control offspring, both under basal conditions and following acute swim stress
Summary
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]. We quantified nine neuroactive steroids (Figure 1) that are known mediators of the stress response, including corticosterone, the end product of HPA axis activation; the positive GABAA receptor modulators, allopregnanolone and THDOC; their precursors, dihydroprogesterone (DHP) and progesterone, as well as dihydrodeoxycorticosterone (DHDOC) and DOC, respectively; and lastly testosterone, which contributes to sex differences in the stress response.[29] These steroids were measured in five distinct brain regions: the hypothalamus, where stress-related circuitry are integrated; the hippocampus, amygdala and the prefrontal cortex, which are limbic areas that together process stressful experiences; and the brainstem, an area that receives inputs regarding homeostatic perturbations.[30] Given allopregnanolone and THDOC potentiate the inhibitory effects of GABA on corticotropin-releasing hormone (CRH) neurones to decrease activity of the HPA axis,[14,16,31] we hypothesised that the concentrations of these 3α,5α-reduced GABAA modulatory neuroactive steroids would be lower in the brains of PNS offspring compared to control offspring following acute stress
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