Abstract | PURPOSE: The goal of the present study was to determine the effects of clozapine (Cloz) and its metabolites norclozapine (Norcloz) and clozapine-N-oxide (Cloz-N- oxide) on the 5-HT(2) receptor system on the levels of protein and gene expression in in vitro systems of primary cortical cells of the rat and human hippocampal SHS5Y5 neuroblastoma cells. METHODS: Clinically relevant concentrations of Cloz (200/400 ng/ml) and its metabolites (200 ng/ml) were used for the examination of the effects of Cloz and its metabolites on serotoninergic 5-HT(2) receptor parameters (density, affinity and mRNA levels) as well as on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels in primary cortical cells of the rat after treatment for 24 h under in vitro conditions. To compare the results to human cells, we also measured treatment-induced changes in 5-HT(2) and GAPDH mRNA levels in human hippocampal SHS5Y5 cells. RESULTS: A significant decrease was found in primary cortical cells for 5-HT(2) receptor density (Cloz 200/Cloz 400/Norcloz 200 and Cloz-N- oxide 200 vs. control) and 5-HT(2A) receptor mRNA levels (Cloz 200 vs. control). 5-HT(2A) receptor mRNA levels were also significantly reduced (Norcloz 200 vs. control) in SHS5Y5 cells. GAPDH mRNA levels were not affected. CONCLUSIONS: The results of the present study show that Cloz and Norcloz induce significant alterations on the 5-HT(2) receptor system in primary cortical cells of the rat and in human hippocampal cells.
|
Authors | Philip Heiser, Eva Schulte, Christiane Hausmann, Ralf Becker, Helmut Remschmidt, Jürgen-Christian Krieg, Helmut Vedder |
Journal | Progress in neuro-psychopharmacology & biological psychiatry
(Prog Neuropsychopharmacol Biol Psychiatry)
Vol. 28
Issue 2
Pg. 297-302
(Mar 2004)
ISSN: 0278-5846 [Print] England |
PMID | 14751426
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- RNA, Messenger
- Receptors, Serotonin, 5-HT2
- Serotonin Antagonists
- norclozapine
- Clozapine
- clozapine N-oxide
|
Topics |
- Analysis of Variance
- Animals
- Cells, Cultured
- Cerebral Cortex
(drug effects, metabolism)
- Clozapine
(analogs & derivatives, metabolism, pharmacology)
- Dose-Response Relationship, Drug
- Gene Expression Regulation
(drug effects)
- Hippocampus
(drug effects, metabolism)
- Humans
- In Vitro Techniques
- Neuroblastoma
- Neurons
(drug effects)
- Protein Binding
(drug effects)
- RNA, Messenger
(biosynthesis)
- Radioligand Assay
(methods)
- Rats
- Receptors, Serotonin, 5-HT2
(drug effects, genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
(methods)
- Serotonin Antagonists
(pharmacology)
|