Pii: S0306-4522(98)00516-8

The effect of prolonged benzodiazepine administration on GABAA receptor subunit (a1–6, b1–3, g2) messenger RNAs was investigated in the rat hippocampus and cortex, among other brain areas. Rats were orally administered flurazepam for one week, a protocol which results in benzodiazepine anticonvulsant tolerance in vivo, and in the hippocampus in vitro, in the absence of behavioral signs of withdrawal. Autoradiographs of brain sections, hybridized with [35S]oligoprobes in situ, were examined immediately (day 0) or two days after drug treatment, when rats were tolerant, or seven days after treatment, when tolerance had reversed, and were compared to sections from pair-handled, vehicle-treated controls. a1 subunit messenger RNA level was significantly decreased in CA1 pyramidal cells and dentate granule cells at day 0, an effect which persisted only in CA1 neurons. Decreased “a1-specific” silver grain density over a subclass of interneurons at the pyramidal cell border suggested concomitant regulation of interneuron GABAA receptors. A reduction in b3 subunit messenger RNA levels was more widespread among hippocampal cell groups (CA1, CA2, CA3 and dentate gyrus), immediately and two days after treatment, and was also detected in the frontal and parieto-occipital cortices. Changes in b2 subunit messenger RNA levels in CA1, CA3 and dentate gyrus cells two days after ending flurazepam treatment suggested a concomitant up-regulation of b2 messenger RNA. There was a trend toward an increased level of a5, b3 and g2 subunit messenger RNAs in CA1, CA3 and dentate gyrus cells, which was significant for the b3 and g2 subunit messenger RNAs in the frontal cortex seven days after ending flurazepam treatment. There were no flurazepam treatment-induced changes in any other GABAA receptor subunit messenger RNAs. The messenger RNA levels of three (a1, b2 and b3) of nine GABAA receptor subunits were discretely regulated as a function of time after ending one-week flurazepam treatment related to the presence of anticonvulsant tolerance, but not dependence. The findings suggested that a localized switch in the subunit composition of GABAA receptor subtypes involving these specific subunits may represent a minimal requirement for the changes in GABAA receptor-mediated function recorded previously at hippocampal CA1 GABAergic synapses, associated with benzodiazepine anticonvulsant tolerance. q 1999 IBRO. Published by Elsevier Science Ltd.