Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions

Stress increases plasma and brain concentrations of corticosteroids and neuroactive steroids. Cortisol is the most important stress hormone in the hypothalamic pituitary adrenocortical system. However, significant amounts of the mineralocorticoid deoxycorticosterone are also released during stress. Deoxycorticosterone undergoes biotransformation to allotetrahydrodeoxycorticosterone, a neuroactive steroid with anxiolytic and anticonvulsant properties. Our studies indicate that the anticonvulsant activity of deoxycorticosterone is mediated by its conversion to allotetrahydrodeoxycorticosterone, which is a potent positive allosteric modulator of GABAA receptors. Although the role of allotetrahydrodeoxycorticosterone within the brain is undefined, recent studies indicate that stress induces increases in allotetrahydrodeoxycorticosterone to levels that can activate GABAA receptors. These results might have significant implications for human stress-sensitive conditions such as epilepsy, panic disorder, post-traumatic stress disorder, and major depression. In epilepsy, a role for adrenal allotetrahydrodeoxycorticosterone in seizure susceptibility has been suggested. Recent preclinical studies indicate a role of neuroactive steroids in ethanol actions. Although these studies provide a better understanding of the role of allotetrahydrodeoxycorticosterone and related neuroactive steroids in acute stress, further studies are clearly warranted to ascertain the specific role of neuroactive steroids in the pathophysiology of chronic stress and related brain conditions.