76 Selective serotonin reuptake inhibitor (SSRI) antidepressants rapidly increase allopregnanolone synthesis, and this may contribute to their anxiolytic effects.77,78 Another neurosteroid, DHEA, which may have “anticortisol” effects, has been reported to be both high and low in depression.17 Notably, both of these

neurosteroids modulate HPA axis activity17,18 and immune system activity,17,79 antagonize oxidative stress17,80 and have certain neuroprotective effects.17,81 Depressed patients entering remission show decreases in plasma cortisol concentrations along with increases in plasma allopregnanolone concentrations.82 Endogenous decreases in this neurosteroid Inhibitors,research,lifescience,medical concentrations or exogenously produced increases in Inhibitors,research,lifescience,medical their concentrations might be expected to have damaging or beneficial effects, respectively, in the context of depression,17,78,83,84 and treatment trials have demonstrated significant antidepressant effects of exogenously administered DHEA.17 Animal models suggest that 3 a hydroxy-5 a reduced steroids (allopregnanolone and allotetrahydrodeoxycorticosterone) are responsive to stress85 and may function to restore normal g-aminobutyric acid (GABA)-ergic

and hypothalamicpituitary-adrenal function following Inhibitors,research,lifescience,medical stress.18,85 In vitro, allopregnanolone suppresses release of gonadotropinreleasing hormone86 or CRH87 via a GABA-A mediated mechanism. Allopregnanolone or allotetrahydrodeoxycorticosterone can also attenuate stress-induced increases Inhibitors,research,lifescience,medical in plasma ACTH and corticosterone and can affect arginine the following site vasopression transcription in the hypothalamus (paraventricular nucleus).18 Under chronic stress or in psychiatric disorders, dysregulation of the HPA axis could be exacerbated if there is insufficient activity of these “counter-regulatory” Inhibitors,research,lifescience,medical neurosteroids. In addition to protection against acute or chronic stress, neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone

may be neuroprotective against early life stressors88 or against deleterious effects Batimastat of social isolation.89 In this way, these neurosteroids may be neuroprotective during development and may affect future responsiveness to stress. The detrimental effects of neurosteroid dysregulation on stress responses has been particularly documented in women with preTofacitinib Citrate solubility menstrual dysphoric disorder (PMDD).90,91 PMDD is a depressive disorder that is characterized by cyclic recurrence, during the luteal phase of the menstrual cycle, of a variety of physical and emotional symptoms that are so severe as to interfere with daily activities. In these studies in women with PMDD, both high and low concentrations of allopregnanolone during the luteal phase of the menstrual have been reported.