Down-regulation of benzodiazepine receptors by ethyl beta-carboline-3-carboxylate in cerebrocortical neurons.
Effect of exposure of primary cultured cerebral cortical neurons to ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of benzodiazepine receptors was studied. Exposure of neurons to beta-CCE (0.1-10 microM) decreased the binding of [3H]flunitrazepam to extensively washed membrane fractions in a dose- and time-dependent manner, whereas the binding of [3H]flunitrazepam to the cytosolic fractions increased (180%) under the same conditions as described above. Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylate (Ro15-1788), an antagonist of the central type of benzodiazepine receptors, completely abolished the beta-CCE-induced decrease in [3H]flunitrazepam binding and the IC50 value for [3H]flunitrazepam binding to the extensively washed membrane fractions prepared from beta-CCE-treated neurons was similar to that from non-treated neurons. Scatchard analysis revealed that only the Bmax value for [3H]flunitrazepam binding decreased after the exposure to beta-CCE (1 microM) for 12 h, although the Kd value was not altered. These results indicate that beta-CCE induces the down-regulation of benzodiazepine receptors by an increase in benzodiazepine receptor internalization.
Katsura
M
M
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
Ohkuma
S
S
Jun
X
X
Kuriyama
K
K
D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D051379:Mice; D011963:Receptors, GABA-A / Q000032:analysis / Q000187:drug effects*
D002243:Carbolines; D011963:Receptors, GABA-A; D005442:Flumazenil; D005445:Flunitrazepam; C024915:beta-carboline-3-carboxylic acid ethyl ester