Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.
N-Methyl-D-aspartate (NMDA, 200 microM) 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 sigma inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of > or = 100 nM. Neither 3 alpha-hydroxy-5 alpha-pregnan-20-one nor its sulfate ester modified NMDA-evoked [3H]NE overflow. The sigma 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-methyl-piperazine. These results indicate that the tested steroid sulfate esters differentially affected the NMDA 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 Gi/o types of guanine nucleotide-binding protein (Gi/o protein) function, suppresses both effects of DHEA S and PREG S. Since sigma 1 but not sigma 2 receptors are coupled to Gi/o proteins, the present results suggest that DHEA S and PREG S control the NMDA response via sigma 1 receptors.
Monnet
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FP
Service de Psychiatrie, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
Mahé
V
V
Robel
P
P
Baulieu
E E
EE
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010052:Ovariectomy; D037342:Pertussis Toxin; D010879:Piperazines / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology*; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology*; D013238:Stereotaxic Techniques; D010566:Virulence Factors, Bordetella / Q000008:administration & dosage / Q000494:pharmacology
C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D006146:Guanidines; D010879:Piperazines; D017450:Receptors, Opioid, mu; D010566:Virulence Factors, Bordetella; C018370:pregnenolone sulfate; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D016202:N-Methylaspartate; D011284:Pregnenolone; D011280:Pregnanolone; D037342:Pertussis Toxin; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D009638:Norepinephrine