NEUROSTEROIDS, VIA SIGMA-RECEPTORS, MODULATE THE [H-3] NOREPINEPHRINE RELEASE EVOKED BY N-METHYL-D-ASPARTATE IN THE RAT HIPPOCAMPUS

N-Methyl-D-aspartate (NMDA, 200 mu M) evokes the release of [H-3]norepinephrine ([H-3]NE) from preloaded hippocampal slices. This effect is potentiated by dehydroepiandrosterone sulfate (DHEA S), whereas it is inhibited by pregnenolone sulfate (PREG S) and the high-affinity sigma inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of greater than or equal to 100 nM. Neither 3 alpha-hydroxy-5 alpha-pregnan-20-one nor its sulfate ester modified NMDA-evoked [H-3] NE overflow. The a antagonists haloperidol and 1-[2-(3,4-dichlorophenyl)-ethyl]-4-methylpiperazine, although inactive by themselves, completely prevented the effects of DHEA S, PREG S, and 1,3-di(2-tolyl)guanidine on NMDA-evoked [3H]NE release. Progesterone (100 nM) mimicked the antagonistic effect of haloperidol and 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine. These results indicate that the tested steroid sulfate esters differentially affected the MMDA response in vitro and suggest that DHEA S acts as a sigma agonist, that PREG S acts as a sigma inverse agonist, and that progesterone may act as a sigma antagonist. Pertussis toxin, which inactivates the G(i/o) types of guanine nucleotide-binding protein (G(i/o) protein) function, suppresses both effects of DHEA S and PREG S. Since sigma(1) but not sigma(2) receptors are coupled to G(i/o) proteins, the present results suggest that DHEA S and PREG S control the NMDA response via sigma(1) receptors.