Neurosteroids in the context of stress: implications for depressive disorders - PubMed (original) (raw)

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Neurosteroids in the context of stress: implications for depressive disorders

Susan S Girdler et al. Pharmacol Ther. 2007 Oct.

Abstract

Animal models indicate that the neuroactive steroids 3alpha,5alpha-THP (allopregnanolone) and 3alpha,5alpha-THDOC (allotetrahydroDOC) are stress responsive, serving as homeostatic mechanisms in restoring normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following stress. While neurosteroid increases to stress are adaptive in the short term, animal models of chronic stress and depression find lower brain and plasma neurosteroid concentrations and alterations in neurosteroid responses to acute stressors. It has been suggested that disruption in this homeostatic mechanism may play a pathogenic role in some psychiatric disorders related to stress. In humans, neurosteroid depletion is consistently documented in patients with current depression and may reflect their greater chronic stress. Women with the depressive disorder, premenstrual dysphoric disorder (PMDD), have greater daily stress and a greater rate of traumatic stress. While results on baseline concentrations of neuroactive steroids in PMDD are mixed, PMDD women have diminished functional sensitivity of GABA(A) receptors and our laboratory has found blunted allopregnanolone responses to mental stress relative to non-PMDD controls. Similarly, euthymic women with histories of clinical depression, which may represent a large proportion of PMDD women, show more severe dysphoric mood symptoms and blunted allopregnanolone responses to stress versus never-depressed women. It is suggested that failure to mount an appropriate allopregnanolone response to stress may reflect the price of repeated biological adaptations to the increased life stress that is well documented in depressive disorders and altered allopregnanolone stress responsivity may also contribute to the dysregulation seen in HPA axis function in depression.

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Figures

Fig. 1

Fig. 1

Allopregnanolone levels in plasma and brain of adult Sprague-Dawley male rats after acute swim stress. Rats were subjected to acute stress by swimming for 10 min in ambient temperature water. Allopregnanolone levels were measured by RIA after purification of the steroid by HPLC. The data represent the mean±SEM for 3 separate experiments (_n_=12 rats per time point) for the cerebral cortex and plasma. Stress-induced increases of allopregnanolone in the cerebral cortex and plasma were statistically significant at 10, 40, and 70 min after the initiation of swim stress compared with nonstressed levels at 0 time [analysis of variance (ANOVA), P<0.05; Tukey's honestly significant difference procedure (HSD), P<0.05]. Adapted from Purdy et al. (1991).

Fig. 2

Fig. 2

Mean±SEM allopregnanolone levels in response to the GnRH test (*, P<0.01 vs. 0 min) and in response to the CRF test (*, P<0.01 vs. 0 min). Adapted from Genazzani et al. (1998).

Fig. 3

Fig. 3

Mean (± SEM) change in luteal phase plasma allopregnanolone (ALLO) during stress in PMDD women and control subjects (#, P<0.010). From Girdler et al. (2001).

Fig. 4

Fig. 4

Allopregnanolone response to the adrenocorticotropic hormone (ACTH) test in patients with premenstrual syndrome (shaded bars) and in the control group (white bars) expressed as area under the curve (*, P<0.05). Adapted from Lombardi et al. (2004).

Fig. 5

Fig. 5

Change (stress−baseline) in allopregnanolone (ALLO) concentrations at 30 and 60 min post-stress in women as a function of histories of depression (DEP). From Klatzkin et al. (2006a).

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