Neonatal exposure to estradiol in rats influences neuroactive steroid concentrations, GABAA receptor expression, and behavioral sensitivity to anxiolytic drugs

Gonadal steroids, in particular estradiol, exert important actions during pre- and perinatal periods in the regulation of sexual dimorphism and development of the nervous system. We have now examined the effects of neonatal estradiol administration in female rats on brain concentrations of the neuroactive steroids allopregnanolone and tetrahydrodeoxycorticosterone, expression of GABA(A) receptor subunits, and behavioral sensitivity to benzodiazepines and allopregnanolone. Administration of beta-estradiol 3-benzoate on the day of birth resulted in marked decreases in the concentrations of progesterone and allopregnanolone in the cerebral cortex at 21, 60, and 180 days after birth. The concentrations of tetrahydrodeoxycorticosterone, 17beta-estradiol, and dehydroepiandrosterone in the brain at 60 days were not affected by such treatment. Neonatal administration of beta-estradiol 3-benzoate also increased the cerebrocortical abundance of alpha(1), alpha(2), and gamma(2) subunits of the GABA(A) receptor without affecting that of alpha(3), alpha(4), alpha(5), or delta subunits. Diazepam induced a greater reduction in locomotor activity as well as a more pronounced anxiolytic-like effect in the elevated plus-maze test in rats subjected to neonatal treatment with beta-estradiol 3-benzoate than in vehicle-treated controls, while allopregnanolone induced a similar effect in both groups. These effects of estradiol suggest that it plays a major role in regulation both of GABAergic transmission and of the abundance of endogenous modulators of such transmission during development of the central nervous system.