title: Inhibitory action of peripheral-type benzodiazepines on dopamine release from PC12 pheochromocytoma cells.
abstract: Characteristics of the benzodiazepine inhibition of dopamine (DA) release in PC12 cells were investigated. Diazepam inhibited DA release evoked by high concentrations of extracellular K+ in a dose-dependent manner (IC50, 10 microM). Ro 5-4864 [7-chloro-1,3-dihydro-1-methyl-5-(p-chlorophenyl)-2H-1,4-benzodiazepine- 2-one], a peripheral-type benzodiazepine, also inhibited DA release effectively. PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinoline carboxamide], a benzodiazepine generally considered a peripheral-type benzodiazepine receptor antagonist, did not antagonize the inhibition induced by diazepam, but rather inhibited DA release itself. On the other hand, the central-type benzodiazepines, clonazepam and Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a] [1,4]benzodiazepine-3-carboxylate) did not affect the DA release. Diazepam, Ro 5-4864 and PK 11195 also inhibited a Ba(++)-current carried by voltage-gated Ca++ channels, and diazepam suppressed an increase in intracellular Ca++ evoked by 80 mM extracellular K+ as measured by the fura-2 method. These results suggest that the inhibitory action of diazepam and other benzodiazepines on DA release from PC12 cells may be mediated through one type of peripheral-type benzodiazepine receptors which are coupled to voltage-gated Ca++ channels and that these receptors may not necessarily be the same as those in other tissues.
authors.affiliation: Division of Pharmacology, National Institute of Hygienic Sciences, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.forename: K
authors.initials: K
authors.lastname: Nakazawa
authors.forename: T
authors.initials: T
authors.lastname: Obama
authors.forename: K
authors.initials: K
authors.lastname: Fujimori
authors.forename: A
authors.initials: A
authors.lastname: Takanaka
authors.forename: K
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001464:Barium / Q000502:physiology; D001569:Benzodiazepines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells / Q000648:ultrastructure*; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D001464:Barium; D003975:Diazepam; D002118:Calcium; D004298:Dopamine