Multifaceted Interaction of Corticosteroids with the Intracellular Receptors and with Membrane GABAA Receptor Complex in the Rat Brain

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Abstract
In vitro assays using crude synaptosomal membrane preparations from the cortex and cytosolic fraction of hippocampus have shown that in the brain, steroids can bind to the intracellular corticosteroid receptors as well as to the membrane-bound GABA-receptor complex. Corticosteroid, deoxycorticosterone and spironolactone bound with higher affinity to the mineralocorticoid (relative binding affinity (IC50 in nM) 1.2, 3.9 and 4.9, respectively) than to the glucocorticoid receptors (IC50 5.2, 14.0 and 88.0 nM, respectively) in hippocampal cytosol. They enhanced significantly the binding of [35S]t-butylbicyclophosphorothionate to cortical membrane. Steroids such as 3α,5α-tetrahydroxydeoxycorticosterone and 3a-hydroxy-5α-dihydroprogesterone displaced the binding of [35S]t-butylbicyclophosphorothionate with IC50 (in nM) of 236.7 and 315.0, respectively. In the presence of 10 to 12.5μM added GABA, they bound with higher affinity (IC50 18.0 and 20.5 nM, respectively). Pentobarbital also bound to this site with IC50 of 430,000 and 240,000 nM, respectively, in the absence and presence of GABA. These compounds also enhanced the binding of [3H]flunitrazepam which was not affected by the presence of added GABA. They showed no affinity for mineralocorticoid or glucocorticoid receptors. Data from this study showed that steroids which preferentially bound to the mineralocorticoid receptor sites (corticosterone, deoxycorticosterone and spironolactone) also enhanced the binding of [35S]t-butylbicyclophosphorothionate to their recognition sites. Steroids which did not interact with the intracellular receptors (3α,5α-tetrahydroxydeoxycorticosterone and 3a-hydroxy-5α-dihydroprogesterone) displaced [35S]t-butylbicyclophosphorothionate binding and enhanced [3H]flunitrazepam binding.