Chronic Treatment with Diazepam or Abecarnil Differentially Affects the Expression of GABAA Receptor Subunit mRNAs in the Rat Cortex

Abstract

Diazepam and abecarnil produce their overt effects by interaction with the GABAA receptor. Chronic treatment with abecarnil, however, does not induce diazepam-like tolerance. This study investigates the effects of chronic diazepam and abecarnil treatment on expression of the GABAA receptor α1–6, β1–3 and γ1–3 subunit isoform mRNAs in rat cortex. Male Sprague-Dawley rats were injected subcutaneously once daily for 7 or 14 days with 15 mg/kg diazepam or 6 mg/kg abecarnil in sesame-oil vehicle, and steady-state levels of GABAA receptor subunit mRNAs were quantified by solution hybridization. The levels of α4-, α5-, β1- and γ3-subunit mRNAs were significantly increased after 7 days of diazepam treatment, and this effect was maintained at 14 days. A significant increase in α3-subunit mRNA was apparent only after 14 days of diazepam treatment and a significant decrease in β2-subunit mRNA was seen only after 14 days of abecarnil treatment. γ2-Subunit mRNA was significantly decreased after 14 days of either diazepam or abecarnil exposure. A degree of association between a particular drug treatment and changes in the levels of mRNAs arising from a given gene cluster was noted. Our results are consistent with a model of diazepam dependence based on GABAA receptor subunit isoform switching. Copyright © 1996 Elsevier Science Ltd