This study has examined whether circulating estrogens are involved in regulating gamma-aminobutyric acid (GABA)A receptor mRNA expression in regions of the female rat brain known to contain estrogen receptors (ERs). In situ hybridization experiments using 35S-labeled oligonucleotides specific for alpha 2, beta 3, and gamma 1 subunit mRNAs of the GABAA receptor demonstrated that all three mRNAs were abundant in only the medial preoptic nucleus (MPN), where they were expressed by the vast majority of cells, and specific regions of the bed nucleus of the stria terminalis including the principle encapsulated nucleus (PrN-BNST) and bed nucleus of the anterior commissure (BNAC). Estrogen treatment of ovariectomized rats for 7 d resulted in significant 30–60% increases in alpha 2 and gamma 1, but not beta 3, subunit mRNA expression in the MPN and PrN-BNST. Estrogen treatment for 24 hr resulted in levels of mRNA expression intermediate between those of controls and animals treated with estrogen for 7 d. No changes in subunit mRNA expression were detected for any subunit in the BNAC or cingulate cortex. Double-labeling immunocytochemistry experiments using antibodies directed against the alpha 2 subunit of the GABAA receptor and the ER, revealed that 67 +/- 3% of alpha 2 subunit-immunoreactive cells in the MPN also contained ER immunoreactivity. Cells expressing alpha 2 subunits in the PrN-BNST were also found to possess ERs while those in the BNAC and cingulate cortex did not. These findings suggest the possibility that ER- containing cells in the MPN and PrN-BNST express an alpha 2 beta 3 gamma 1 isoform of the GABAA receptor that has its alpha 2 and gamma 1 subunits regulated by circulating estrogen concentrations. Together, our observations indicate that estrogen may regulate GABAA receptor mRNA expression at a transcriptional level and that this is only likely to occur within regions of the rat brain possessing ERs.