BRAIN AREA-SPECIFIC DIFFERENCES IN THE EFFECTS OF NEUROACTIVE STEROIDS ON THE GABA(A) RECEPTOR COMPLEXES FOLLOWING ACUTE TREATMENT WITH ANAESTHETICALLY ACTIVE STEROIDS

Regional differences in the effects of neuroactive steroids on the GABA(A) receptor complex have been demonstrated in vitro (1-3). In order to elucidate if a regionally different modulation of the GABA-binding site also occurs after acute steroidal treatment, in the present study the effects of systemically applied progesterone (10 mg/kg body wt) and its metabolite 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha,5alpha-THP) (2 mg/kg body wt) on the specific [H-3]muscimol binding to the GABA-binding site was evaluated using membrane fractions prepared from five different brain areas of ovariectomized rats. The receptor density (mumol/kg protein) was not affected in all brain areas investigated by treatment with 3alpha,5alpha-THP but was enhanced selectively in the frontal cortex and hippocampus of progesterone-treated animals. A decrease of affinity was observed in medulla after application of progesterone or 3alpha,5alpha-THP, in contrast to the hypothalamus, which was the single region exhibiting an increase of affinity after steroidal administration. In the frontal cortex and hippocampus only the injection of progesterone reduced the affinity. whereas in cerebellum both steroidal treatments were incapable of affecting the affinity. These regional differences in response to the GABA-binding site to acutely applied progesterone and 3alpha,5alpha-THP are consistent with the existence of heterogeneous populations of GABA(A) receptor-coupled steroid-binding sites.