Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA-receptor function.
1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg-1 day-1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg-1 i.p., and GABA-dependent chloride uptake in 3 brain regions at these time points. 3. Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872-resistant (Type 2) sites in both regions. Maximal GABA-dependent chloride uptake was also decreased in the cortex and hippocampus at day 7. 4. Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA-dependent chloride uptake was also decreased only in the cortex. 5. These data suggest that the effects of chronic benzodiazepine administration on the GABAA-receptor may be both region-specific and receptor subtype-specific.
Galpern
W R
WR
Department of Psychiatry, Tufts University School of Medicine, Boston, MA.
Miller
L G
LG
Greenblatt
D J
DJ
Shader
R I
RI
D000525:Alprazolam / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D005442:Flumazenil / Q000378:metabolism; D008140:Lorazepam / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects*
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D008140:Lorazepam; D000525:Alprazolam