Down-regulation of benzodiazepine binding to alpha 5 subunit-containing gamma-aminobutyric Acid(A) receptors in tolerant rat brain indicates particular involvement of the hippocampal CA1 region.
Chronic benzodiazepine treatment can produce tolerance and changes in gamma-aminobutyric acid (GABA)(A) receptors. To study the effect of treatment on a selected population of receptors, assays were performed using [(3)H]RY-80, which is selective for GABA(A) receptors with an alpha 5 subunit. Rats were given a flurazepam treatment known to produce tolerance and down-regulation of benzodiazepine binding, or a diazepam treatment shown to produce tolerance but not receptor down-regulation. Quantitative receptor autoradiography using sagittal brain sections bound with [(3)H]RY-80 showed binding in areas known to express alpha 5 mRNA. Brains from flurazepam-treated rats showed significantly decreased 1 nM [(3)H]RY-80 binding in hippocampal formation (e.g., 32% decrease in CA1) and superior colliculus, but not other areas. Using 5 nM [(3)H]RY-80 showed similar decreases in hippocampus. A corresponding 29% decrease in B(max) but no change in K(d) was found with a filtration binding assay using hippocampal homogenates. Down-regulation of [(3)H]RY-80 binding had returned to control by 2 days after withdrawing flurazepam treatment. The magnitude of down-regulation of [(3)H]RY-80 binding suggested that GABA(A) receptors with an alpha 5 subunit may play a prominent role in the adaptive responses associated with benzodiazepine tolerance. Chronic diazepam treatment also resulted in decreased [(3)H]RY-80 binding. However, the regional selectivity was even more pronounced than in flurazepam-treated rats, and only the hippocampal CA1 region showed decreased binding (27%). This localized down-regulation persisted for several days after the end of diazepam treatment. These data indicate that synapses in the hippocampal CA1 region are particularly involved in the adaptive response to chronic benzodiazepine treatments.
Li
M
M
Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo, Ohio 43614-5804, USA.
Szabo
A
A
Rosenberg
H C
HC
D000480:Alkynes; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000494:pharmacology*; D001345:Autoradiography; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D005445:Flunitrazepam / Q000378:metabolism; D005479:Flurazepam / Q000378:metabolism / Q000494:pharmacology; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D014316:Tritium
D000480:Alkynes; D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D007093:Imidazoles; C109021:RY 80; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D005445:Flunitrazepam; D005479:Flurazepam; D003975:Diazepam