THE INFLUENCE OF ESTRUS CYCLE ON NEUROSTEROID POTENCY AT THE GAMMA-AMINOBUTYRIC ACIDA RECEPTOR COMPLEX

The reduced metabolites of progesterone (3alpha-hydroxy-5alpha-pregnan -20-one or 3alpha,5alpha-P) and deoxycorticosterone (3alpha,21-dihydro xy-5alpha-pregnan-20-one or 5alpha-THDOC) exhibit a gamma-aminobutyric acid (GABA) agonist pharmacological profile and bind with high affini ty to a unique steroid recognition site on the GABA(A) receptor comple x (GRC). In female rats, peak levels of 3alpha,5alpha-P occur between proestrus and estrus and at concentrations which appear sufficient to affect GRC-mediated inhibitory events. Therefore, steroid modulation o f the binding of [S-35]t-butylbicyclophosphorothionate was conducted t o examine sensitivity of the GRC during the estrus cycle. The results in unwashed tissue (cortex, cerebellum, hippocampus and striatum) indi cated that 3alpha,5alpha-P was most potent in estrus. Subsequent studi es ir washed tissue and in washed tissue plus 3 muM (+)bicuculline ind icated that 3alpha,5alpha-P was more potent in diestrus 1 than in estr us. Brain regional differences in potency of 3alpha,5alpha-P were also observed. Overall, the results in washed tissue suggest that an inher ent change in the sensitivity of the GRC occurs during the estrus cycl e, whereas the results in unwashed tissue may be influenced by the pre sence of endogenous GRC-active neurosteroids and GABA. The change in s ensitivity of the GRC during the estrus cycle may occur to help mainta in homeostatic regulation of brain excitability.