title: In vivo labeling of the central GABA uptake carrier with 3H-Tiagabine.
abstract: The in vivo binding of 3H-Tiagabine to the central GABA uptake carrier in mouse brain was characterized. 3H-Tiagabine in vivo bound to a single class of binding sites with a Kd = 72.5 nM and a Bmax = 640 pmol/g tissue. 3H-Tiagabine binding in vivo was regionally distributed within the CNS, and showed a good correlation with 3H-Tiagabine binding in vitro. Pharmacological characterization of 3H-Tiagabine binding in vivo revealed a binding site exhibiting specificity for GABA uptake inhibitors. Experiments examining the in vivo receptor occupancy of the GABA uptake carrier for a series of GABA uptake inhibitors revealed that 20-30% of the GABA uptake sites were occupied at the ED50 for inhibiting DMCM-induced clonic convulsions, while a 50-62% receptor occupancy in vivo was needed to inhibit rotarod performance. These data suggest that 3H-Tiagabine in vivo binding may be a useful method for assessing GABA uptake inhibitor penetration into the CNS, and may be a useful tool for studying the physiological regulation of the GABA uptake carrier.
authors.affiliation: Department of Receptor Neurochemistry, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: K E
authors.initials: KE
authors.lastname: Andersen
authors.forename: L J
authors.initials: LJ
authors.lastname: Knutsen
authors.forename: C
authors.initials: C
authors.lastname: Braestrup
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D007274:Injections, Intraperitoneal; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000378:metabolism*; D027361:Organic Anion Transporters; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002243:Carbolines; D002352:Carrier Proteins; D003292:Convulsants; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; D000078308:Tiagabine