383. Differential cloning and DNA microarrays in depression research

Abstract

Depression is one of the major psychiatric diseases. Although blockade by antidepressants of monoamine uptake into nerve endings is one of the cornerstones of the monoamine hypothesis of depression, there is a clear discrepancy between the rapid effects of antidepressants in increasing synaptic concentrations of monoamine and the lack of immediate clinical efficiency of antidepressant treatment. It is known that antidepressant effect is generally observed after repeated administration for several weeks. This delay could be explained at the molecular level by an action on gene transcription. Recently introduced technique, DNA microarray, enabled us to perform large-scale coordinate monitoring of gene expression during different functional states in normal and diseased samples, or in control and treated animals. This method of large-scale gene expression analysis creates a bridge between the molecular pharmacological approach and study at the systems level to understand the pathophysiology of depression and the mechanisms of action of the treatment. In addition to the gene expression monitoring, cDNA microarray can be used for gene discovery by probing enriched libraries derived from the experiments with differential cloning techniques, which includes Differential Display PCR, RNA fingerprinting, Suppressive Subtractive Hybridization, and Representational Difference Analysis. While screening of the common biochemical changes induced after antidepressant treatment in rat brain with these genome-pharmacological approach, we identified several interesting candidate genes and expressed sequence tags, ESTs. We believe that these molecules would be attractive target molecules for future antidepressant development with a new class of action in the brain.