title: Acute treatment with pentobarbital alters the kinetics of in vivo receptor binding in the mouse brain.
abstract: The effect of pentobarbital, a sedative-hypnotic barbiturate, on the in vivo binding of benzodiazepine receptors in the mouse brain was investigated. Dose-related changes in the apparent binding of [3H]Ro15-1788 ([3H]flumazenil) in the cerebral cortex, cerebellum and pons-medulla were observed by pretreatment with pentobarbital. For quantification of the kinetic properties of the in vivo binding of [3H]Ro15-1788, time courses of radioactivity following its injection were examined, and kinetic analysis was performed using the compartment model. The time courses of radioactivity following injection of [3H]Ro15-1788 with 3 mg/kg Ro15-1788 were used as input function. In all regions studied, rate constants between input compartment and specific binding compartment were significantly decreased by pentobarbital. However, no significant alterations in the binding potential (BP=K3/K4) of benzodiazepine receptors by pentobarbital were observed in any of the regions. A saturation experiment indicated that the decrease in the input rate constant (K3), which includes both the association rate constant (k(on)) and the number of binding sites available (B(max)), was mainly due to decrease in k(on). These results suggest that apparent increases in binding at 20 min after tracer injection were due to the decrease in the association and dissociation rates of binding in vivo.
authors.affiliation: Division of Clinical Research, National Institute of Radiological Sciences, Inage-ku, Chibashi 263-8555, Japan. yojiro.sakiyama@pfizer.com
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Sakiyama
authors.forename: Masao
authors.initials: M
authors.lastname: Saito
authors.forename: Osamu
authors.initials: O
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000493:pharmacokinetics*; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010424:Pentobarbital / Q000008:administration & dosage*; D011485:Protein Binding; D011865:Radioisotope Dilution Technique; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D014316:Tritium; D005442:Flumazenil; D010424:Pentobarbital