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 application is limited because with daily use tolerance develops to certain aspects of its pharmacological profile. We compared the effects of two dosing paradigms on GABA(A) receptor gene expression and benzodiazepine binding characteristics. Equivalent daily doses of 15 mg/kg/day diazepam were delivered either via constant infusion or daily subcutaneous injection for 14 days. The two distinct treatment regimes produced significantly different changes in GABA(A) receptor alpha4-, beta2-, beta3- and gamma1-subunit mRNA steady-state levels. Similar changes in the GABA enhancement of flunitrazepam binding and the BZ3/BZ2 subtype ratio determined ex vivo were produced, however, significant differences were found in [(3)H]-Ro 15-4513 binding between cortical tissue from diazepam injected animals compared with diazepam infused animals. Our data suggest that it is the diurnal fluctuations in receptor occupancy that are responsible for the different effects produced by these two dosing regimes.
Arnot
M I
MI
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Davies
M
M
Martin
I L
IL
Bateson
A N
AN
D000345:Affinity Labels / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D014316:Tritium
D000345:Affinity Labels; D001386:Azides; D018757:GABA Modulators; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; C042957:Ro 15-4513; D003975:Diazepam