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The influence of estrus cycle on neurosteroid potency at the gamma-aminobutyric acidA receptor complex.

The reduced metabolites of progesterone (3 alpha-hydroxy-5 alpha-pregnan-20-one or 3 alpha,5 alpha-P) and deoxycorticosterone (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one or 5 alpha-THDOC) exhibit a gamma-aminobutyric acid (GABA) agonist pharmacological profile and bind with high affinity to a unique steroid recognition site on the GABAA receptor complex (GRC). In female rats, peak levels of 3 alpha,5 alpha-P occur between proestrus and estrus and at concentrations which appear sufficient to affect GRC-mediated inhibitory events. Therefore, steroid modulation of the binding of [35S]t-butylbicyclophosphorothionate was conducted to examine sensitivity of the GRC during the estrus cycle. The results in unwashed tissue (cortex, cerebellum, hippocampus and striatum) indicated that 3 alpha, 5 alpha-P was most potent in estrus. Subsequent studies in washed tissue and in washed tissue plus 3 microM (+)bicuculline indicated that 3 alpha,5 alpha-P was more potent in diestrus 1 than in estrus. Brain regional differences in potency of 3 alpha,5 alpha-P were also observed. Overall, the results in washed tissue suggest that an inherent change in the sensitivity of the GRC occurs during the estrus cycle, whereas the results in unwashed tissue may be influenced by the presence of endogenous GRC-active neurosteroids and GABA. The change in sensitivity of the GRC during the estrus cycle may occur to help maintain homeostatic regulation of brain excitability.