Interaction of 3β, 5α-tetrahydrodeoxycorticosterone in rat and guinea-pig neurons:: a comparison of Ca2+- and GABAA-Cl--channel current modulation

A comparison of the interaction of 3 beta, 5 alpha-tetrahydrodeoxycorticosterone (TDOC) on voltage-gated Ca2+- and the gamma-aminobutyric receptor (GABA,) gated-Cl--channels was examined in freshly dissociated guinea-pig (GP) and rat hippocampal CA1 neurons and rat hypothalamic ventromedial nucleus (VMN) neurons. The steady-state inhibition of the peak Ca2+ channel current evoked by depolarized steps from -80 to -10 mV by TDOC increased in concentration-dependent manner with IC50 values of 1 and 6 pM for rat and GP CA1 neurons, respectively and 3 nM for rat VMN neurons. TDOC rapidly and reversibly inhibited a fi action (up to 26%) of the total Ca2+ channel current in all neurons. Intracellular dialysis with GDP-beta-S (500 mu M) significantly diminished the TDOC inhibition of the Ca2+ channel current, suggesting a G-protein involvement. In neurons isolated from pertussis-toxin-treated animals by chronic intracerebroventricular (1000 ng/24/48 h) infusion, the TDOC inhibition was also significantly diminished, suggesting modulation by the G alpha(i) and/or G alpha(0) G-protein subunits. The peak GABA-gated inward Cl- current was enhanced in both species from 0.1 to 10 mu M with the greatest increase (48% at 10 mu M) seen in the VMN. There was no difference in the enhancement of the GABA current in the CA1 region of both species. The results show that in contrast to the 3 alpha-series, the 3 beta-series weakly enhance the GABA-evoked Cl- current but potently inhibit the Ca2+ channel current. In addition, these results also suggest a common mode of action and a lack of interspecies difference for this steroid. (C) 1999 Elsevier Science Inc. All rights reserved.