Abstract

Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive steroid with antagonist action at γ-aminobutyric acid type A (GABA_A) receptors. Patch-clamp techniques were used to investigate DHEAS actions at GABA_A receptors of the rat pituitary gland at two distinct loci: posterior pituitary nerve terminals and intermediate pituitary endocrine cells. The GABA responses in these two regions were quite different, with posterior pituitary responses having smaller amplitudes and desensitizing more rapidly and more completely. DHEAS blockade of GABA_Areceptors in the two regions also was different. In posterior pituitary, a site with an apparent dissociation constant of 15 μM accounted for most of the blockade, but a small fraction of blockade may be related to a site with a dissociation constant in the nanomolar range. In the intermediate lobe, DHEAS sensitivities in the nanomolar and micromolar ranges were clearly evident, in proportions that varied widely from cell to cell. Regardless of whether the GABA response of a cell was highly sensitive or weakly sensitive to DHEAS, GABA alone evoked currents that were indistinguishable in terms of amplitude, desensitization kinetics, and GABA sensitivity. Thus, the structural elements responsible for DHEAS blockade have a highly selective impact on receptor function. GABA_A receptors with nanomolar sensitivity to DHEAS have not been described previously. This suggests that DHEAS may have an important role in the modulation of neuropeptide secretion, and the diverse properties of GABA_A receptors in the rat pituitary provide mechanisms for selective regulation of the different peptidergic systems of this gland.