Heterogeneity of gamma-aminobutyric acid/benzodiazepine/beta-carboline receptor complex in rat spinal cord.
The properties of muscimol, beta-carboline (BC), and benzodiazepine (BZD) binding to crude synaptic membranes were studied in the spinal cord and cerebellum of rats. In cerebellar membranes, the density of high-affinity [3H]muscimol and [3H]6,7-dimethoxy-4-ethyl-beta-carboline ([3H]BCCM) binding sites is almost identical to that of [3H]flunitrazepam ([3H]FLU) or [3H]flumazenil (Ro 15-1788; ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1-4]benzodiazepine-3-carboxylate). In contrast to the cerebellum, the number of muscimol and BC binding sites in rat spinal cord is approximately 20-25% of the number of FLU or flumazenil binding sites. Moreover, in spinal cord membranes, BC recognition site ligands displace [3H]-flumazenil bound to those sites, with low affinity and a Hill slope significantly less than 1; the potency of the different BCs in displacing [3H]flumazenil is 20-50-fold lower in the spinal cord than in the cerebellum. [3H]Flumazenil is not displaced from spinal cord membranes by the peripheral BZD ligand Ro 5-4864 (4'-chlorodiazepam), whereas it is displaced with low affinity and a Hill slope of less than 1 (nH = 0.4) by CL 218,872 (3-methyl-6-(3-trifluoromethylphenyl)-1,2,4-triazolol[4,3-b] pyridazine). These data suggest that a large number of BZD binding sites in spinal cord (approximately 80%) are of the central-type, BZD2 subclass, whereas the BZD binding sites in cerebellum are predominantly of the central-type, BZD1 subclass.(ABSTRACT TRUNCATED AT 250 WORDS)
Santi
M R
MR
Fidia-Georgetown Institute for the Neurosciences, Georgetown University Medical School, Washington, D.C. 20007.
Cox
D H
DH
Guidotti
A
A
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001667:Binding, Competitive; D002243:Carbolines / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D005442:Flumazenil / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism*; D008297:Male; D009118:Muscimol / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002243:Carbolines; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D009118:Muscimol; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D003975:Diazepam; D001640:Bicuculline