Pregnenolone sulfate antagonizes dizocilpine amnesia: role for allopregnanolone.
Pregnenolone (PREG) is metabolized in brain to progesterone (PROG), 5 alpha-dihydroprogesterone (5 alpha-DHP) and allopregnanolone (ALLO). Infusion of adrenalectomized/castrated rats with PREG sulfate prevented the cognition deficit elicited by the ionotropic glutamate receptor antagonists, dizocilpine and CPPene. Using a new gas chromatographic/mass-spectrometric method, we demonstrated that PREG sulfate infusion markedly increased the PREG, PROG, 5 alpha-DHP and ALLO brain content. The increase in 5 alpha-DHP and ALLO, but not PREG or PROG content and the antagonism of dizocilpine amnesia observed by injecting rats with PREG sulfate was reversed by inhibiting the conversion of PROG to 5 alpha-DHP with the 5 alpha-reductase blocker SKF 105111. We and others have shown that ALLO potently modulate GABAA receptor function whereas 5 alpha-DHP fails to induce rapid changes in neurotransmitter receptor function. Thus it is possible to suggest that the increase in the brain content of ALLO, rather than 5 alpha-DHP, mediates the effect of PREG sulfate on dizocilpine- or CPPene-induced cognition deficit.
Nathan S. Kline Institute for Psychiatric Research, Center for Neuropharmacology, Orangeburg, NY 10962, USA.
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Cheney
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Uzunov
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Guidotti
D000647:Amnesia / Q000139:chemically induced*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D011280:Pregnanolone / Q000494:pharmacology*; D011284:Pregnenolone / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
D014151:Anti-Anxiety Agents; D016291:Dizocilpine Maleate; D011284:Pregnenolone; D011280:Pregnanolone