Transcriptomics of Antipsychotic Drug Function: What have we Learned from Rodent Studies?

Elizabeth      A. Thomas

doi:10.2174/2211556011201040272

Abstract

Antipsychotic medications remain the first-line treatment for several psychiatric disorders. These compounds, classified as typical or atypical antipsychotics, have well-established neurotransmitter receptor binding profiles; however, long-term therapeutic benefits likely result from molecular changes in the brain occurring downstream from receptor blockade. In the past decade, researchers have utilized high-throughput gene expression approaches to study post-receptor mechanisms of antipsychotic drug function and have implicated several systems, including synaptic- and ubiquitinationrelated pathways, in the mechanisms of actions of antipsychotic drugs. In recent years, additional transcriptome data from updated and improved microarray platforms have been published. The most widely studied antipsychotics have been haloperidol, olanzapine and clozapine, representing both typical and atypical drugs, and several studies have highlighted both the similarities and differences in the transcriptome profiles associated with both classes of drugs. Furthermore, some studies have additionally investigated the effects of antipsychotic drugs in combination with psychostimulant exposure to rodents, in order to identify convergent gene expression alterations. This review will summarize recent transcriptomewide studies that have investigated differential gene expression in response to antipsychotic drug treatment in rodent brain, highlighting the most reproducible findings across studies. Emerging evidence has also suggested that epigenetic mechanisms of gene regulation are associated with antipsychotic drug action; this will also be reviewed herein. Examination of transcriptomic profiles of antipsychotic drug action should reveal key information regarding the beneficial mechanisms associated with drug treatment and may reveal gene ‘signatures’ for known drugs, which could be used to develop improved therapeutics.

Keywords: Psychiatric, transcriptomics, gene expression, neuroleptic, ion channel, synaptic function, Antipsychotic Drug, psychiatric illness, antipsychotics, Microarray studies, schizophrenia, dopamine neurons, neuroleptics, D2 receptors, psychiatric disorders