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Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro.

AbstractPURPOSE:
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.
AuthorsPhilip Heiser, Eva Schulte, Christiane Hausmann, Ralf Becker, Helmut Remschmidt, Jürgen-Christian Krieg, Helmut Vedder
JournalProgress in neuro-psychopharmacology & biological psychiatry (Prog Neuropsychopharmacol Biol Psychiatry) Vol. 28 Issue 2 Pg. 297-302 (Mar 2004) ISSN: 0278-5846 [Print] England
PMID14751426 (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)

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