CHRONIC TREATMENT WITH DIAZEPAM OR ABECARNIL DIFFERENTIALLY AFFECTS THE EXPRESSION OF GABA(A) RECEPTOR SUBUNIT MESSENGER-RNAS IN THE RAT CORTEX

Diazepam and abecarnil produce their overt effects by interaction with the GABA(A) receptor. Chronic treatment with abecarnil, however, does not induce diazepam-like tolerance. This study investigates the effec ts of chronic diazepam and abecarnil treatment on expression of the GA BA(A) receptor alpha 1-6, beta 1-3 and gamma 1-3 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 abecarni l in sesame-oil vehicle, and steady-state levels of GABA(A) receptor s ubunit mRNAs were quantified by solution hybridization. The levels of alpha 4-, alpha 5-, beta 1- and gamma 3-subunit mRNAs were significant ly increased after 7 days of diazepam treatment, and this effect was m aintained at 14 days. A significant increase in alpha 3-subunit mRNA w as apparent only after 14 days of diazepam treatment and a significant decrease in beta 2-subunit mRNA was seen only after 14 days of abecar nil treatment. gamma 2-Subunit mRNA was significantly decreased after 14 days of either diazepam or abecarnil exposure. A degree of associat ion between a particular drug treatment and changes in the levels of m RNAs arising from a given gene cluster was noted. Our results are cons istent with a model of diazepam dependence based on GABA(A) receptor s ubunit isoform switching. Copyright (C) 1996 Elsevier Science Ltd.