Differential effect of dehydroepiandrosterone and its steroid precursor pregnenolone against the behavioural deficits in CO-exposed mice

The neuroactive steroids pregnenolone (3 beta-hydroxy-5-pregnen-20-one) and dehydroepiandrosterone (DHEA, 3 alpha-hydroxy-5-androstene-17-one) are neg ative allosteric modulators of the GABA(A) receptors and positive modulator s of acetylcholine, NMDA and sigma(1) receptors. Pregnenolone was recently shown to potentiate the neuronal damage induced by excessive glutamate in c ell culture models, whereas dehydroepiandrosterone was reported to present some neuroprotective activity. The in vivo relevance of these effects was i nvestigated in mice submitted to an hypoxic insult, the repeated exposure t o carbon monoxide (CO) gas, a model that leads to neurodegeneration in the CA(1) hippocampal area and learning deficits. Recording spontaneous alterna tion behaviour in the Y-maze assessed short-term memory and long-term memor y was examined using a passive avoidance task. After exposure to CO, mice s howed a progressive deterioration of their learning ability, reaching signi ficance after 3 days and being maximal after 7 days. Pregnenolone administe red before CO significantly facilitated the hypoxia-related deficits, which could be measured 1 day after CO and appeared maximal after 3 days. Dizoci lpine blocked the deficits in vehicle- and pregnenolone-treated CO-exposed animals, showing that pregnenolone selectively facilitated the NMDA recepto r- dependent excitotoxicity. Dehydroepiandrosterone blocked the appearance of the CO-induced deficits, even after 7 days. Interestingly, the sigma(1) receptor antagonist N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethy lamine (NE-100) failed to affect the dehydroepiandrosterone-induced protect ion, showing the lack of involvement of sigma(1) receptors. Cresyl violet-s tained sections of the mouse hippocampal formation showed that the neurodeg eneration observed in the CA(1) area after exposure to CO was augmented by pregnenolone and blocked by dehydroepiandrosterone. These results show that pregnenolone and dehydroepiandrosterone, although being similarly involved in modulating the excitatory/inhibitory balance in the brain, do not equal ly affect the extent of excitotoxic insults. (C) 2000 Elsevier Science B.V. All rights reserved.