Benzodiazepine enhancement of gamma-aminobutyric acid-mediated chloride ion flux in rat brain synaptoneurosomes.
Benzodiazepine agonists such as Ro 11-6896 [B10(+)], diazepam, clonazepam, and flurazepam were found to enhance muscimol-stimulated 36Cl- uptake into rat cerebral cortical synaptoneurosomes. The rank order of potentiation was B10(+) greater than diazepam greater than clonazepam greater than flurazepam. These benzodiazepines had no effect on 36Cl-uptake in the absence of muscimol. Further, the inactive enantiomer, Ro 11-6893 [B10(-)], and the peripheral benzodiazepine receptor ligand Ro 5-4864 did not potentiate muscimol-stimulated 36Cl- uptake at concentrations up to 10 microM. In contrast, the benzodiazepine receptor inverse agonists ethyl-beta-carboline-3-carboxylate and 6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylic acid methyl ester inhibited muscimol stimulated 36Cl- uptake. Benzodiazepines and beta-carbolines altered the apparent K0.5 of muscimol-stimulated 36Cl- uptake, without affecting the Vmax. The effects of both benzodiazepine receptor agonists and inverse agonists were reversed by the benzodiazepine antagonists Ro 15-1788 and CGS-8216. These data further confirm that central benzodiazepine receptors modulate the capacity of gamma-aminobutyric acid receptor agonists to enhance chloride transport and provide a biochemical technique for studying benzodiazepine receptor function in vitro.
Morrow
A L
AL
Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892.
Paul
S M
SM
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004357:Drug Synergism; D005479:Flurazepam / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001570:Benzodiazepinones; D002243:Carbolines; D002712:Chlorides; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; C040696:Ro 11-6893; C024915:beta-carboline-3-carboxylic acid ethyl ester; D005479:Flurazepam; D003975:Diazepam