PREGNENOLONE SULFATE ANTAGONIZES DIZOCILPINE AMNESIA - ROLE FOR ALLOPREGNANOLONE

PREGNENOLONE (PREG) is metabolized in brain to progesterone (FROG), 5 alpha-dihydroprogesterone (5 alpha-DHP) and allopregnanolone (ALLO). I nfusion of adrenalectomized/castrated rats with PREG sulfate prevented the cognition deficit elicited by the ionotropic glutamate receptor a ntagonists, dizocilpine and CPPene. Using a new gas chromatographic/ma ss-spectrometric method, we demonstrated that PREG sulfate infusion ma rkedly increased the PREG, PROG, 5 alpha-DHP and ALLO brain content. T he increase in 5 alpha-DHP and ALLO, but not PREG or FROG content and the antagonism of dizocilpine amnesia observed by injecting rats with PREG sulfate was reversed by inhibiting the conversion of PROG to 5 al pha-DHP with the 5 alpha-reductase blocker SKF 105111. We and others h ave shown that ALLO potently modulate GABA(A) receptor function wherea s 5 alpha-DHP fails to induce rapid changes in neurotransmitter recept or function. Thus it is possible to suggest that the increase in the b rain content of ALLO, rather than 5 alpha-DHP, mediates the effect of PREG sulfate on dizocilpine- or CPPene-induced cognition deficit.