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
Abstract
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 γ-aminobutyric acid (GABA) type-A receptors, as well as in decreases in the abundance of GABAA receptor α1, α3, α5, and γ2 subunit mRNAs. These effects were accompanied by decreases in the efficacies of diazepam and the β-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 α4 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 5α-reductase inhibitor finasteride also prevented the changes in both GABAA receptor gene expression and receptor function elicited by progesterone treatment and withdrawal.
Footnotes
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Send reprint requests to: Dr. Paolo Follesa, Department of Experimental Biology, University of Cagliari, 09123 Cagliari, Italy. E-mail:follesa{at}vaxca1.unica.it
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This study was supported by Grant 9905045782 from Ministero dell'Università e della Ricerca Scientifica e Tecnologica (Projects of National Relevance, Article 65DPR 382/80).
- Abbreviations:
- GABA
- γ-aminobutyric acid
- AP
- allopregnanolone
- CNS
- central nervous system
- DMCM
- methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate
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- Received September 27, 1999.
- Accepted February 12, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
