Inhibitory effects of clozapine and other antipsychotic drugs on noradrenaline transporter in cultured bovine adrenal medullary cells.
The effects of clozapine and other antipsychotic drugs on noradrenaline (NA) transport were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NA transporter. Incubation of adrenal medullary cells with clozapine (30-1000 ng/ml) inhibited desipramine (DMI)-sensitive uptake of [3H]NA in a concentration-dependent manner (IC50=110 ng/ml or 336 nM). Other antipsychotic drugs such as haloperidol, chlorpromazine, and risperidone also decreased [3H]NA uptake (IC50= 144, 220, and 210 ng/ml or 383, 690, and 512 nM, respectively). Eadie-Hofstee analysis showed that clozapine reduced V(max) of uptake of [3H]NA and increased K(m). Furthermore, clozapine inhibited specific binding of [3H]DMI to plasma membranes isolated from bovine adrenal medulla (IC50=48 ng/ml or 146 nM). Scatchard plot analysis of [3H]DMI binding revealed that clozapine decreased both B(max) and K(d). Other antipsychotic drugs, including haloperidol, chlorpromazine, and risperidone, also reduced [3H]DMI binding to the membranes. In transfected Xenopus oocytes expressing the bovine NA transporter, clozapine inhibited [3H]NA uptake in a concentration-dependent manner similar to that observed in adrenal medullary cells. These results suggest that clozapine and haloperidol directly inhibit transport of NA by acting on the site of an NA transporter that influences both substrate transport and binding of tricyclic antidepressants.
Yoshimura
R
R
Department of Psychiatry, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka, Japan.
Yanagihara
N
N
Hara
K
K
Terao
T
T
Nakamura
J
J
Ueno
S
S
Toyohira
Y
Y
Uezono
Y
Y
Kaneko
S
S
Kawamura
M
M
Abe
K
K
Izumi
F
F
D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002417:Cattle; D002478:Cells, Cultured; D003024:Clozapine / Q000494:pharmacology*; D003891:Desipramine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007700:Kinetics; D009638:Norepinephrine / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027981:Symporters; D014316:Tritium; D014981:Xenopus
D014150:Antipsychotic Agents; D002352:Carrier Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; D014316:Tritium; D003024:Clozapine; D006220:Haloperidol; D003891:Desipramine; D009638:Norepinephrine