Elsevier

Biological Psychiatry

Volume 57, Issue 9, 1 May 2005, Pages 1041-1051
Biological Psychiatry

Original articles
Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat

https://doi.org/10.1016/j.biopsych.2005.01.022Get rights and content

Background

Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs.

Methods

Gene expression analysis was performed with the Affymetrix U34A array in the frontal cortex (FC) and the striatum of rats chronically treated with two concentrations of either clozapine or haloperidol. Key data were verified with real-time quantitative polymerase chain reaction.

Results

Many genes in the FC affected by APD-treatment contribute to similar functions. mRNAs coding for synaptic vesicle docking- and microtubule-associated proteins were upregulated; mRNAs for serine-threonine protein phosphatases were downregulated, whereas the serine-threonine kinases protein kinase A, protein kinase C, and calcium/calmodulin kinase II alpha and IV were upregulated, indicating increased potential for protein phosphorylation. In the striatum, altered gene expression was less focused on genes of particular function or location, and the high concentration of haloperidol had a different gene expression profile than any of the other APD treatments.

Conclusion

We found an increase in the transcription of genes coding for proteins involved in synaptic plasticity and synaptic activity in the FC. We furthermore found that the gene expression profile of APDs is different between FC and striatum.

Section snippets

Animals

Male Sprague-Dawley rats (Taconic Farms, Germantown, New York) weighing 200 g at the beginning of the experiment were housed four to a cage on a 12-hour light-dark cycle. The animals were allowed 1 week for habituation to the colony before the first drug administration. All rats received single, daily injections, administered intraperitoneally (IP). Animal care and experimental procedures conformed to PHS Policy on Humane Care and Use of Laboratory Animals.

Results

A triple data analysis was performed with dChip, MAS 5.0 and RMAExpress. Most differences in expression levels of abundantly expressed genes treated with APDs and analyzed with dChip 1.3 were below twofold. Genes with lower expression levels and high signal-to-noise ratios yielded higher-fold differences. For example, syntaxin 12 was expressed eightfold higher in the FC of APD treated rats than in vehicle-treated control subjects but was above detection level in only 9 of 28 samples (32%

Discussion

Changes in mRNA levels have been previously correlated with similar changes in protein levels. For example, acute treatment with haloperidol caused upregulations of c-fos, proenkephalin, and synapsin II mRNAs that translated into upregulations of these proteins in the striatum (Chong et al 2002; Dragunow et al 1990; Hong et al 1979, 1985; Konradi and Heckers 1995; Konradi et al 1993; Leveque et al 2000). Although these findings are encouraging for microarray experiments, it is important to keep

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