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Present address: Psychobiologie des Comportements Adaptatifs, INSERM, Unite 259, Universite de Bordeaux II, Domaine de Carriere, Rue Camille Saint-Saens, Bordeaux, 33077, France
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Steroid structure and pharmacological properties determine the anti-amnesic effects of pregnenolone sulphate in the passive avoidance task in rats
Article first published online: 6 JAN 2002
DOI: 10.1046/j.0953-816x.2001.01817.x
Additional Information
How to Cite
Vallée, M., Shen, W., Heinrichs, S. C., Zorumski, C. F., Covey, D. F., Koob, G. F. and Purdy, R. H. (2001), Steroid structure and pharmacological properties determine the anti-amnesic effects of pregnenolone sulphate in the passive avoidance task in rats. European Journal of Neuroscience, 14: 2003–2010. doi: 10.1046/j.0953-816x.2001.01817.x
Publication History
- Issue published online: 6 JAN 2002
- Article first published online: 6 JAN 2002
- Received 26 June 2001, revised 28 September 2001, accepted 29 October 2001
- Abstract
- Article
- References
- Cited By
Keywords:
- neurosteroid;
- memory;
- pregnenolone sulphate enantiomers;
- NMDA receptors;
- scopolamine;
- passive avoidance;
- rats
Abstract
Pregnenolone sulphate (PREGS) 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 PREGS is a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of γ-aminobutyric acidA receptors (GABAARs). Moreover, PREGS is able to reverse the amnesic-like effects of NMDAR and GABAAR ligands. To investigate this hypothesis, the present study in rats examined the memory-altering abilities of structural analogs of PREGS, which differ in their modulation of NMDAR and/or GABAAR function. The analogs tested were: 11-ketopregnenolone sulphate (an agent that is inactive at GABAARs and NMDARs), epipregnanolone ([3β-hydroxy-5β-pregnan-20-one] sulphate, an inhibitor of both GABAARs and NMDARs), and a newly synthesized (–) PREGS enantiomer (which is identical to PREGS in effects on GABAARs and NMDARs). The memory-enhancing effects of PREGS and its analogs were tested in the passive avoidance task using the model of scopolamine-induced amnesia. Both PREGS and its (–) enantiomer blocked the effects of scopolamine. The results show that, unlike PREGS, 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 PREGS. Moreover, enantioselectivity was demonstrated by the ability of natural PREGS 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.