Dual phases of functional change in norepinephrine transporter in culturedbovine adrenal medullary cells by long-term treatment with clozapine

Citation
R. Yoshimura et al., Dual phases of functional change in norepinephrine transporter in culturedbovine adrenal medullary cells by long-term treatment with clozapine, J NEUROCHEM, 77(4), 2001, pp. 1018-1026
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROCHEMISTRY
ISSN journal
0022-3042 → ACNP
Volume
77
Issue
4
Year of publication
2001
Pages
1018 - 1026
Database
ISI
SICI code
0022-3042(200105)77:4<1018:DPOFCI>2.0.ZU;2-C
Abstract
The effects of long-term treatment with clozapine, a prototype of atypical antipsychotic drugs, on the functional activity, synthesis acid mRNA of nor epinephrine (NE) transporter were examined in bovine adrenal medullary cell s in culture. Treatment of cells with clozapine at 0.1-3.0 muM concentratio ns produced dual phases of changes in [H-3]NE uptake, i.e. the first phase showed a decrease in [H-3]NE uptake at 2-48 h, and the following phase show ed an increase in uptake at 72-163h. Treatment with clozapine for 6 h decre ased V-max to 40% of the control without changing the K-m value for [H-3]NE uptake. However, treatment with clozapine for 96 h increased V-max by 56% over the control without a change in K-m. Scatchard plot analysis of [H-3]d esipramine (DMI) binding to membranes isolated from cells treated with cloz apine for 6 h revealed a decrease in B-max without any change in K-d; in co ntrast, treatment with clozapine for 96 h caused an increase in B-max witho ut any change in K-d. Both actinomycin D and cycloheximide, which are inhib itors of protein synthesis, suppressed the clozapine (96 h)-induced increas e in [H-3]NE uptake. Treatment of cells with clozapine for 12-96 h increase d the level of NE transporter mRNA in a concentration-dependent manner (0.3 -3.0 muM). These findings suggest that treatment of cells with clozapine re sults in the down-regulation and subsequent up-regulation of NE transporter . The latter change may be caused by the synthesis of new proteins of NE tr ansporter via an increase in its mRNA.