Influence of gender and brain region on neurosteroid modulation of GABA responses in rats

Abstract

Neuroactive steroid derivatives of progesterone, testosterone and glucocorticoids can alter physiological responses to γ-aminobutyric acid (GABA), apparently through direct, non-steroid receptor mechanisms. The present study examined gender-related differences and regional variations in the ability of tetrahydrodeoxycorticosterone (THDOC), 3α-hydroxy-5α-pregnan-20-one (3α-5α-THP, tetrahydroprogesterone), androsterone, and dihydroandrosterone (DHA) to alter physiological GABA responses. Steroid modulation of GABA-activated 36chloride influx into microsac preparations from cortex, hippocampus, amygdala, cerebellum and hypothalamus-preoptic area in adrenalectomized-gonadectomized rats of both sexes were tested. The effects of THDOC and 3α-5α-THP were also examined in groups of intact male and female rats. All four steroids increased GABA-activated chloride influx, although the maximal enhancement in GABA responses differed significantly among brain regions. The rank order of maximal THDOC and 3α-5α-THP effects was hippocampus > cortex ~ amygdala > hypothalamus-preoptic area ~ cerebellum. Regional differences in potentiation of GABA responses were seen with androsterone, but not dihydroandrosterone. The rank order of androgenic potentiation of GABA responses was amygdala ~ hippocampus > cortex ~HPA > cerebellum. Slight gender-related differences in responses to steroids were seen with THDOC, with males showing greater maximal enhancement of GABA responses with THDOC than females in the amygdala and hypothalamus-preoptic area. Since sex differences were observed with the glucocorticoid derivative THDOC, but not the progesterone derivative 3α-5α-THP or androgenic steroids, it appears neuroactive steroid modulation of GABA responses can be differentially affected by the hormonal milieu in a regionally-specific manner.