Decoding the transcriptional programs activated by psychotropic drugs in the brain.

ABSTRACT

Analysis of drug-induced gene expression in the brain has long held the promise of revealing the molecular mechanisms of drug actions as well as predicting their long-term clinical efficacy. However, despite some successes, this promise has yet to be fulfilled. Here, we present an overview of the current state of understanding of drug-induced gene expression in the brain and consider the obstacles to achieving a robust prediction of the properties of psychoactive compounds based on gene expression profiles. We begin with a comprehensive overview of the mechanisms controlling drug-inducible transcription and the complexity resulting from expression of noncoding RNAs and alternative gene isoforms. Particular interest is placed on studies that examine the associations within drug classes with regard to the effects on gene transcription, alterations in cell signaling and neuropharmacological drug properties. While the ability of gene expression signatures to distinguish specific clinical classes of psychotropic and addictive drugs remains unclear, some reports show that under specific constraints, drug properties can be predicted based on gene expression. Such signatures offer a simple and effective way to classify psychotropic drugs and screen novel psychoactive compounds. Finally, we note that the amount of data regarding molecular programs activated in the brain by drug treatment has grown exponentially in recent years and that future advances may therefore come in large part from integrating the currently available high-throughput data sets.