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Differential display polymerase chain reaction reveals increased expression of striatal rat glia-derived nexin following chronic clozapine treatment

The Pharmacogenomics Journal volume 4, pages 379–387 (2004)Cite this article

ABSTRACT

Clozapine is considered a prototype of the ‘so-called’ atypical antipsychotic drug class. It has affinity for a broad range of receptors and, in comparison to typical antipsychotic drugs, produces less extrapyramidal side effects. However, its mechanism of action remains unclear. Differential display polymerase chain reaction (ddPCR) was implemented in this study to contribute to the current understanding of this mechanism at the genetic level and to identify novel genes regulated by clozapine. This technique generated approximately 2400 gene sequences that were analyzed for differential gene expression following protracted clozapine treatment. One of these sequences, originally termed Clozapine Regulated Gene (CRG), was shown to be significantly upregulated following the treatment. Northern hybridization confirmation of this finding revealed that chronic clozapine administration caused a five-fold increase in CRG mRNA. Elongation of the 5′- and 3′-ends of CRG indicated that the fragment was in fact rat glia-derived nexin mRNA. Western blotting demonstrated that levels of the mRNA's associated protein also increased comparably (three-fold) following chronic treatment with the antipsychotic drug. This study presents a possible neuroprotective role of nexin in clozapine treatment, particularly in the prevention of neuronal proteolytic degradation, since nexin has been shown to be a protease inhibitor.

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Abbreviations

CRG:

clozapine regulated gene

ddPCR:

differential display polymerase chain reaction

RACE-PCR:

rapid amplification of cDNA ends polymerase chain reaction

RGDN:

rat glia-derived nexin

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Acknowledgements

This work was supported by the Ontario Mental Health Foundation and National Institutes of Health (USA). RKM is a recipient of the senior fellowship of the Ontario Mental Health Foundation. VZC is a recipient of the NSERC Canada Graduate Scholarship.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada

    V Z Chong, W Costain, J Marriott, S Sindwani, D MacCrimmon & R K Mishra

  2. Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA, USA

    D J Knauer

  3. Centre for Addiction and Mental Health (Clarke Site), Toronto, ON, Canada

    J-F Wang & L T Young

Authors
  1. V Z Chong
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  2. W Costain
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  3. J Marriott
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  4. S Sindwani
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  5. D J Knauer
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  6. J-F Wang
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  7. L T Young
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  8. D MacCrimmon
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  9. R K Mishra
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Correspondence to R K Mishra.

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None declared.

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Chong, V., Costain, W., Marriott, J. et al. Differential display polymerase chain reaction reveals increased expression of striatal rat glia-derived nexin following chronic clozapine treatment. Pharmacogenomics J 4, 379–387 (2004). https://doi.org/10.1038/sj.tpj.6500274

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