GABA(A) receptor gene expression in rat cortex: Differential effects of two chronic diazepam treatment regimes

Diazepam is widely prescribed as an anxiolytic but its therapeutic applicat ion is limited because with daily use tolerance develops to certain aspects of its pharmacological profile. We compared the effects of two dosing para digms on GABA(A) receptor gene expression and benzodiazepine binding charac teristics. Equivalent daily doses of 15 mg/kg/day diazepam were delivered e ither via constant infusion or daily subcutaneous injection for 14 days. Th e two distinct treatment regimes produced significantly different changes i n GABA(A) receptor alpha4-, beta2-, beta3- and gamma1-subunit mRNA steady-s tate levels. Similar changes in the GABA enhancement of flunitrazepam bindi ng and the BZ3/BZ2 subtype ratio determined ex vivo were produced, however, significant differences were found in [H-3]-Ro 15-4513 binding between cor tical tissue from diazepam injected animals compared with diazepam infused animals. Our data suggest that it is the diurnal fluctuations in receptor o ccupancy that are responsible for the different effects produced by these t wo dosing regimes. (C) 2001 Wiley-Liss, Inc.