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A Rapid New Assay to Detect RNA Editing Reveals Antipsychotic-Induced Changes in Serotonin-2C Transcripts

Departments of Pharmacology and Psychiatry, Vanderbilt University, Nashville, Tennessee (M.S.K.S., D.C.A., E.S.-B.); Vanderbilt Kennedy Center for Research on Human Development, Nashville, Tennessee (W.L., E.S.-B.); and Department of Psychiatry, University of Oxford, Oxford, United Kingdom (P.W.J.B., P.J.H.)

We report the development of a new assay as an alternative to direct DNA sequencing to measure RNA-edited variation in tissue. The new assay has been validated and is accurate, cheaper, more rapid, and less labor-intensive than DNA sequencing. We also outline the statistical modeling required for analyses of the hierarchical, clustered RNA-editing data generated in these studies. Using the new technique, we analyzed the effects of long-term antipsychotic medication on serotonin-2C receptor (5-HT_2CR) RNA editing in rat brain. Our hypothesis that a drug with high affinity for 5-HT_2CR, such as clozapine, would alter its RNA-editing profile was not confirmed. Whereas haloperidol, a typical antipsychotic drug that is primarily a dopamine receptor antagonist, reduced 5-HT_2C VNV isoform frequency and the level of RNA editing at the D site, risperidone and not the prototype atypical antipsychotic drug clozapine increased the frequency of 5-HT_2C VNV and D-site editing. Our data emphasize that caution is required in the interpretation of RNA-editing data in studies of psychiatric disorders, because these studies usually include subjects who received long-term exposure to medication. This newly established method will facilitate high-throughput investigations of RNA editing in disease pathology and in the pharmacological activity of drugs.

Address correspondence to: Dr. Monsheel Sodhi, Departments of Psychiatry and Pharmacology, Vanderbilt University, 8148 Medical Research Building III, 465 21st Avenue South, Nashville, TN 37212. E-mail: monsheel.sodhi{at}vanderbilt.edu

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