However, 3α,5α-THP levels in post-mortem human brain are similar to rat brain and sufficient to have GABAergic activity29 Table I summarizes the effects of acute stress on neuroactive steroid levels in rodents, monkeys, and humans. The increase in neuroactive steroid levels elicited by stressful stimuli, Tenofovir supplier including ethanol administration,

appears to be mediated by activation Inhibitors,research,lifescience,medical of the hypothalamic-pituitaryadrenal (HPA) axis, since it is no longer apparent in adrenalectomized animals.18,30,31 Adrenalectomized animals exhibit no circulating concentrations of 3α,5α-THP and 3α,5α-THDOC, but brain levels are still detectable,18 suggesting that brain synthesis plays an important role in neurosteroid actions. Indeed, brain synthesis of 3α,5α-THP can be increased by ethanol in adrenalectomized Inhibitors,research,lifescience,medical immature animals allowed sufficient time for adaptation,32 suggesting that brain synthesis of neurosteroids may exhibit plasticity in response to physiological challenges. Table I. Summary of the changes Inhibitors,research,lifescience,medical in neuroactive steroids and their precursors in rats, monkeys, and healthy human subjects induced by acute ethanol

administration or by acute stress or HPA stimulation. These effects are described and referenced in the text. ↑ … Neuroactive steroids and the HPA axis The activation of the HPA axis in response to acute stress increases the release of CRF from Inhibitors,research,lifescience,medical the hypothalamus, which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary; this, in turn, stimulates the adrenal cortex to release glucocorticoids, neuroactive steroid precursors, and GABAergic neuroactive steroids. Glucocorticoids, mainly Cortisol in humans and nonhuman primates, and corticosterone in Inhibitors,research,lifescience,medical rodents, provide negative feedback on the hypothalamus and pituitary. Likewise, GABAergic neuroactive steroids inhibit CRF production and release, ACTH release, and subsequent corticosterone levels in rodents.33-35 The

ability of neuroactive steroids to reduce HPA axis activation may play an important role in returning the animal to homeostasis following stressful events. This physiological coping response appears to be critical for mental health, since it is dysregulated in various mood disorders, including depression, post-traumatic before stress disorder, and premenstrual dysphoric disorder (PMDD). Neuroactive steroid concentrations are altered in various pathophysiological conditions that involve dysfunction of the HPA axis. The HPA axis plays an important role in the pathophysiology of depression: patients with major depression have elevated Cortisol levels, a consequence of hypersecretion of CRF due to lowered feedback mechanisms,36 which also contributes to a blunted dexamethasone response.