Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain.

Abstract

A 3a-hydroxy A-ring-reduced metabolite of progesterone, 3a-hydroxy-5a-pregnan-20-one (allopregnanolone), and one of deoxycorticosterone (DOC), 3a,21-dihydroxy-5a-pregnan-20-one (ailotetrahydroDOC), are among the most potent known ligands of y-aminobutyric acid (GABA) receptors designated GABAA in the central nervous system. With specific radioimmunoassays, rapid (<5 min) and robust (4-to 20-fold) increases of allopregnanolone and allotetrahydroDOC were detected in the brain (cerebral cortex and hypothalamus) and in plasma of rats after exposure to ambient temperature swim stress. Neither steroid was detectable in the plasma of adrenalectomized rats either before or after swim stress. However, allopregnanolone, but not allotetrahydro-DOC, was still present in the cerebral cortex (>3 ng/g) after adrenalectomy. These data demonstrate the presence of allopregnanolone and allotetrahydroDOC in brain and show that acute stress results in a rapid increase of these neuroactive steroids to levels known to modulate GABAA receptor function.It has been almost 50 years since Selye (1) reported the anesthetic and sedative properties of several 3a-hydroxy A-ring-reduced pregnane steroids, including the major metabolites of progesterone, 3a-hydroxy-5a-pregnan-20-one (allopregnanolone) and 3a-hydroxy-5p-pregnan-20-one (pregnanolone), and the major metabolite of deoxycorticosterone (DOC), 3a,21-dihydroxy-5a-pregnan-20-one (allotetrahydroDOC). In addition to their sedative-hypnotic and anesthetic effects, these steroids have subsequently been shown to produce a number of other behavioral effects when administered to laboratory animals, including anticonflict (2), anticonvulsant (3), and analgesic actions (4). The behavioral effects of these 3a-hydroxysteroids do not appear to involve genomic events that are mediated by steroid receptors since they occur quite rapidly (seconds to minutes) after parenteral administration, and since neither steroid binds with appreciable affinity to progesterone receptors (5). Recently, we and others (6-13) have reported that allopregnanolone and allotetrahydroDOC bind with high affinity to recognition sites associated with the y-aminobutyric acid (GABA) receptor complex. The GABAA receptor is one of two known receptors for GABA, the principal inhibitory neurotransmitter in brain, and has been shown to mediate the anxiolytic, sedative, and hypnotic actions of many drugs, including benzodiazepines and anesthetic barbiturates (14, 15). Radioligand binding and Cl-flux studies (6-12) as well as electrophysiologic experiments in cultured embryonic neurons (16) have provided evidence for the presence of unique and perhaps multiple steroid recognition sites (13) associated with the GABAA receptor macromolecular complex. In experiments using recombinantly expressed GABAA receptors, both allopregnanolone and allotetrahydroDOC were effective in potentiating GABA-activated Cl-currents at low nanomolar concentrations, comparable to the most potent benzodiazepines (17).The relatively high affinity of th...

Neurosteroids in the context of stress: Implications for depressive disorders

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