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Vol. 57, Issue 6, 1262-1270, June 2000

Allopregnanolone Synthesis in Cerebellar Granule Cells: Roles in Regulation of GABAA Receptor Expression and Function during Progesterone Treatment and Withdrawal

Paolo Follesa, Mariangela Serra, Elisabetta Cagetti, Maria Giuseppina Pisu, Stefania Porta, Stefania Floris, Federico Massa, Enrico Sanna, and Giovanni Biggio

Department of Experimental Biology "Bernardo Loddo," University of Cagliari, Cagliari, Italy

Rat cerebellar granule cells were cultured for 5 days with progesterone, resulting in the conversion of progesterone to allopregnanolone, a potent and efficacious modulator of gamma -aminobutyric acid (GABA) type-A receptors, as well as in decreases in the abundance of GABAA receptor alpha 1, alpha 3, alpha 5, and gamma 2 subunit mRNAs. These effects were accompanied by decreases in the efficacies of diazepam and the beta -carboline DMCM with regard to modulation of GABA-evoked Cl- currents. Withdrawal from such progesterone treatment resulted in a rapid and selective increase in the abundance of the GABAA alpha 4 subunit mRNA that was associated with a restoration of receptor sensitivity to the negative modulatory action of DMCM, a positive receptor response to flumazenil, and continued reduced responsiveness of receptors to diazepam. Prevention of allopregnanolone synthesis by the 5alpha -reductase inhibitor finasteride also prevented the changes in both GABAA receptor gene expression and receptor function elicited by progesterone treatment and withdrawal.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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