Dehydroepi-androsterone (DHEA) exhibits various behavioral effects in mammals, at least one of which is enhancement of memory that appears to be mediated by an interaction with the gamma-aminobutyr...

DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range.

Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and estrogenic steroids. DHEA/S concentrations are particularly high in the brain, and DHEA/S and related steroids can be synthesized de novo in brain glial cells. Therefore, the term neurosteroids' has been coined for these compounds. This review summarizes findings in neurosteroid physiology on a cellular and molecular level, and outlines current concepts of how these compounds modulate physiological functions of the brain. Today, despite promising preclinical and human data the present clinical studies provide only weak evidence, if any, in favour of a DHEA replacement therapy.

Dehydroepiandrosterone--a neurosteroid.

There is still controversy about the influence of ageing on the activity of the hypothalamo-pituitary-adrenocortical (HPA) axis in the rat. The first objective of the present study was to evaluate the influence of ageing on the activity of the HPA axis by measuring pituitary proopiomelanocortin (POMC, the precursor of ACTH and alphaH) mRNA levels in the anterior and intermediate lobes in young (50-55-day old) and aged (18-month-old) rats of both sexes. The second goal of the study was to evaluate the effect of 2.5 day administration of dehydroepiandrosterone (DHEA), a steroid precursor which has been shown to improve some ageing-associated deficits. In the young male anterior pituitary, DHEA induced a 17.5% increase in POMC mRNA levels. In aged males, anterior pituitary POMC mRNA levels were 22% lower than those detected in young animals. DHEA treatment produced a 26% increase, then completely restoring mRNA levels when compared to those found in young vehicle-treated males. In the young female, DHEA did not induce any changes in anterior pituitary POMC mRNA. In aged females a 24% reduction in the hybridization signal was observed. This reduction was completely reversed by DHEA which induced a 45% increase over the levels observed in vehicle-treated aged animals. In the intermediate lobe, the results were very similar to those obtained in the anterior lobe, although the observed effects induced by ageing and DHEA were less striking. These results together with previous ones indicating an age-related decrease in corticotropin-releasing hormone (CRH) neuronal activity suggest that ageing is associated with a decrease in HPA axis activity. They also demonstrate that a short-term DHEA treatment can exert a beneficial influence by reversing the decrease in pituitary POMC mRNA expression which occurs as a consequence of ageing.

Effects of ageing and dehydroepiandrosterone administration on pro-opiomelanocortin mRNA expression in the anterior and intermediate lobes of the rat pituitary.

The aim of this project was to investigate the possible mechanism(s) underlying the attenuated hypothalamic-pituitary-adrenal (HPA) axis response to stressors during pregnancy at the level of the anterior pituitary. We found that the reduced HPA axis activity during pregnancy was not due to changes in the sensitivity of corticotrophs in the anterior pituitary, but to the decreased secretion particularly of vasopressin and possibly corticotropin-releasing hormone (CRH) from the hypothalamus. The reduced CRH and vasopressin secretion during pregnancy is a result of action of neurosteroid metabolites of progesterone as a 5a-reductase inhibitor reversed the attenuated adrenocorticotrophic hormone (ACTH) secretory response to stress. By in situ hybridisation, we found a progressive decrease in proopiomelanocortin (POMC) mRNA expression in the anterior pituitary during pregnancy. However, there was no change in ACTH content. Compared with expression in the anterior pituitary of virgin rats, in late pregnancy (day 21), CRH receptor subtype 1 (CRHR1) mRNA expression was not changed, vasopressin receptor subtype lb (VlbR) mRNA expression was reduced, and glucocorticoid receptor (GR) mRNA was increased. We also measured large conductance potassium channel (BK) and the splice variant of the BK channel, STREX, mRNA expression and found no change during pregnancy. Corticotropin-releasing hormone binding protein (CRHBP) mRNA expression was elevated by 30 min restraint stress in the anterior pituitary, but there were no differences between virgin and pregnant rats. In vivo, a CRHR1 antagonist, antalarmin, decreased ACTH secretion in response to swimming stress in both virgin and pregnant rats. However, a Vla/b receptor antagonist decreased the ACTH response to this stressor in virgin rats only. Exogenous vasopressin or CRH injection alone increased ACTH secretion more in virgin than in pregnant rats. Injection of CRH and vasopressin together had a similar stimulatory action on ACTH secretion in virgin and pregnant rats. Thus the attenuated ACTH stress response during pregnancy is primarily a result of reduced vasopressin secretion during stress.

Mechanism(s) underlying the attenuated ACTH responses to stress in pregnancy

Steroid receptor-mediated effects of neuroactive steroids: characterization of structure-activity relationship.

Brain-derived steroids (neurosteroids) constitute a new group of steroids synthesized in brain cells independently from peripheral sources. While the membraneous actions of these steroids have been characterized in some detail, their genomic effects are less well studied up to now. In the present study, the action of the neurosteroids dehydroepiandrosterone, pregnenolone and pregnanolone on proopiomelanocortin (POMC)-gene expression was investigated in pituitary AtT 20 cells, which were cultured under serum-free conditions and at strictly controlled steroid levels. In these cells, POMC-gene expression is known to be negatively regulated by adrenocortical glucocorticoids. Quantitative Northern blot analysis showed that none of these neurosteroids or their conjugates affected POMC-mRNA levels even at the highest concentrations employed. The 21-OH steroid corticosterone was used as a control and markedly suppressed the synthesis of POMC-mRNA. These results suggest that neurosteroids do not control POMC-gene expression at the level of the pituitary corticotroph and exclude significant effects of these compounds at the glucocorticoid receptor.

Neurosteroids do not regulate proopiomelanocortin-gene expression in pituitary cells.

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Neurosteroids do not regulate proopiomelanocortin-gene expression in pituitary cells.