Neurosteroids: Pregnenolone and Dehydroepiandrosterone in the Brain

Brain testosterone and corticosteroids arise from peripheral sources, whereas pregnenolone (Δ5-P) and dehydroepiandrosterone (DHA), the 3β-hydroxy-Δ5 derivatives of cholesterol which serve as precursors of steroid hormones in steroidogenic glands, accumulate in the brain by proper mechanism(s), even after surgical or pharmacological suppression of endocrine glands (adrenals, gonads). They are found in definite proportions as free steroids, or sulfate and fatty acid esters. Two enzymes involved in side-chain cleavage, cytochrome P-450 and adrenodoxin, have been immunohistochemi-cally localized in white matter, suggesting a possible modulatory/ trophic general function; they were also present in a few neurons of the olfactory bulb, entorhinal cortex and cingulum, evoking an olfactory pathway. The “neurosteroid” concept is based on changes observed in a variety of physiological situations, including diurnal rhythm, development, and heterosexual exposure of male to female rats. Pharmacologically, DHA decreased a particular type of male mice agressive behavior linked to lactating female signal. The mode of action of Δ5-P and DHA is yet unknown. It may include their transformation to classical steroid hormones acting on a paracrine mode, or directly their binding to unknown membrane or intra-cellular receptors, or even the control of neuronal functions by their insertion into membranes.