Steroid structure and pharmacological properties determine the anti-amnesic effects of pregnenolone sulphate in the passive avoidance task in rats

Pregnenolone sulphate (DREGS) has generated interest as one of the most potent memory-enhancing neurosteroids to be examined in rodent learning studies, with particular importance in the ageing process. The mechanism by which this endogenous steroid enhances memory formation is hypothesized to involve actions on glutamatergic and GABAergic systems. This hypothesis stems from findings that DREGS is a potent positive modulator of N-methyl-D-aspartate receptors (NMDARs) and a negative modulator of gamma -aminobutyric acid(A) receptors (GABA(A)Rs). Moreover, DREGS is able to reverse the amnesic-like effects of NMDAR and GABA(A)R ligands. To investigate this hypothesis, the present study in rats examined the memory-altering abilities of structural analogs of DREGS, which differ in their modulation of NMDAR and/or GABA(A)R function. The analogs tested were: 11-ketopregnenolone sulphate (an agent that is inactive at GABA(A)Rs and NMDARs), epipregnanolone ([3 beta -hydroxy-5 beta -pregnan-20-one] sulphate, an inhibitor of both GABA(A)Rs and NMDARs), and a newly synthesized (-) PREGS enantiomer (which is identical to DREGS in effects on GABA(A)Rs and NMDARs). The memory-enhancing effects of DREGS and its analogs were tested in the passive avoidance task using the model of scopolamine-induced amnesia. Both DREGS and its (-) enantiomer blocked the effects of scopolamine. The results show that, unlike DREGS, 11-ketopregnenolone sulphate and epipregnanolone sulphate failed to block the effect of scopolamine, suggesting that altering the modulation of NMDA receptors diminishes the memory-enhancing effects of DREGS. Moreover, enantioselectivity was demonstrated by the ability of natural DREGS to be an order of magnitude more effective than its synthetic enantiomer in reversing scopolamine-induced amnesia. These results identify a novel neuropharmacological site for the modulation of memory processes by neuroactive steroids.