Electrophysiological effects of various neuroactive steroids on the GABA(A) receptor in pituitary melanotrope cells.

The action of steroids on the bioelectrical response to gamma-aminobutyric acid (GABA) has never been studied in pituitary cells. In the present study, we have thus investigated the effects of a series of neuroactive steroids on the GABA-activated current in frog melanotrope cells in primary culture, using the patch-clamp technique in the whole-cell configuration. Bath perfusion of 3alpha-isomers of pregnanolone or tetrahydrodeoxycorticosterone (1 microM) significantly enhanced the current evoked by short pulses of GABA (3 microM) and accelerated its desensitization. In contrast, the 3beta-isomers (30 microM) had no effect on the GABA-activated current. Addition to the bath solution of dehydroepiandrosterone or dehydroepiandrosterone sulfate (10 microM) inhibited the GABA-activated current without modifying its kinetics while pregnenolone sulfate (10 microM) both inhibited the GABA-activated current and accelerated its decay rate. The effects of pregnane steroids were not impaired by the central-type benzodiazepine receptor antagonist flumazenil (10 microM). In conclusion, the present study reveals that neuroactive steroids may exert multiple modulatory activities on the GABA(A) receptor borne by melanotrope cells. The effect of steroids on the current evoked by GABA is rapid, reversible, stereospecific and not mediated through the benzodiazepine binding site of the GABA(A) receptor.