Effects of zotepine and olanzapine on noradrenaline transporter in cultured bovine adrenal medullary cells.
BACKGROUND
Previously, it was demonstrated that the inhibitory effects of atypical antipsychotic drugs such as clozapine and risperidone on noradrenaline transporter (NAT) might in part be associated with their clinical profile. The present study examined the effects of zotepine on NAT in the cells and compared them with those of olanzapine.


METHODS
Adrenal medullary cells were isolated by a method of collagenase digestion of slices of fresh bovine adrenal medulla and the cells were plated at a density of 4 x 10(6) cells. Cells were incubated with [3H]noradrenaline (NA) in the presence or absence of zotepine or olanzapine. The amount of radioactivity taken into the cells was counted by a liquid scintillation counter. Plasma membranes of bovine adrenal medulla were prepared, and the binding of [3H]desipramine (DMI) was determined by incubating the membrane suspension in binding buffer together with zotepine or olanzapine. Specific binding of [3H] DMI was defined as that binding which was inhibited by nisoxetine.


RESULTS
Both zotepine (10-1000 ng/ml) and olanzapine (10-1000 ng/ml) decreased [3H]NA uptake in a concentration-dependent manner. The IC50 values of zotepine and olanzapine on [3H]NA uptake were 10 +/- 4 and 14 +/- 8 ng/ml, respectively. Eadie-Hofstee analysis of [3H]NA uptake showed that treatment with zotepine and olanzapine decreased the V(max) of uptake without changing the K(m). Both zotepine (10-1000 ng/ml) and olanzapine (30-1000 ng/ml) inhibited [3H]DMI binding in a concentration-dependent manner. The IC50 values of zotepine and olanzapine on [3H]DMI binding were 50 +/- 18, and 120 +/- 38 ng/ml, respectively. Scatchard plot analysis of [3H]DMI binding showed that zotepine and olanzapine decreased the B(max) of binding without altering the K(d).


CONCLUSIONS
The inhibitory effects of zotepine and olanzapine might be responsible in part for their clinical profile.
Yoshimura
Reiji
R
Department of Psychiatry, University of Occupational and Enviromental Health, School of Medicine, Kitakyushu, Japan. yoshi621@med.uoeh-u.ac.jp
Shinkai
Koji
K
Toyohira
Yumiko
Y
Ueno
Susumu
S
Yanagihara
Nobuyuki
N
Nakamura
Jun
J
D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D003891:Desipramine / Q000378:metabolism; D003988:Dibenzothiepins / Q000494:pharmacology*; D007700:Kinetics; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D000077152:Olanzapine
D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D001569:Benzodiazepines; D000077152:Olanzapine; D003891:Desipramine; C022172:zotepine; D009638:Norepinephrine