Neurosteroids, via σ Receptors, Modulate the [3H]norepinephrine Release Evoked by N-Methyl-D-Aspartate in the Rat Hippocampus

N-Methyl-D-aspartate (NMDA, 200 μM) evokes the release of [3H]norepinephrine ([3H]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 σ inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of ≥100 nM. Neither 3α-hydroxy-5α-pregnan-20-one nor its sulfate ester modified NMDA-evoked [3H]NE overflow. The σ 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 NMDA response in vitro and suggest that DHEA S acts as a σ agonist, that PREG S acts as a σ inverse agonist, and that progesterone may act as a σ antagonist. Pertussis toxin, which inactivates the Gi/otypes of guanine nucleotide-binding protein (Gi/oprotein) function, suppresses both effects of DHEA S and PREG S. Since σ1but not σ2receptors are coupled to Gi/oproteins, the present results suggest that DHEA S and PREG S control the NMDA response via σ1receptors.