GABAA receptor changes in acute allopregnanolone tolerance

To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90min of anaesthesia. Acute tolerance was demonstrated at 90min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor Subunit alpha 4mRNA amount in the thalamus ventral-posteriornedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha(4) subunit was detected with immohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha(4)mRNA in the thalaruUS ventral-posterionicdial nucleus, and positively correlated with alpha(2)mRNA in different hippocarripal subregions. There was also a positive relationship between the alpha(1) mRNA amounts in the different hippocampal subre ions. with significant differences between groups. These changes in GABAA receptor Subunits mRNA expression and protein (alpha(4)) might be of importance for the development of acute tolerance to allopregnanolone. (c) 2006 Elsevier B.V All rights reserved.