Altered Gene Expression in Antidepressant Treatment

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (As provided by the Applicant): Current pharmacological treatments of depression are faced with two major problems: first, chronic exposure to antidepressant drugs is required to produce therapeutic effects and, second, the nature and frequency of side-effects from all available drug regimens still represent the main reason for noncompliance to treatment in depressed patients. Accordingly, the search for new generations of antidepressant drugs represents a major effort in both pharmaceutical and academic research. Currently, mechanistic working models for antidepressant action are mostly centered on the serotonin system. These models include increased serotonergic tone, decreased pre-synaptic serotonin1A receptor function and plastic changes in diverse 5-HT projection areas. In our work, we describe a rodent behavioral model, the "Novelty Suppressed Feeding" (NSF),that mimics the delayed onset and therapeutic effects of several antidepressant drug treatments in human patients. We also describe preliminary results of large-scale gene expression profile, in response to different drug treatments and/or genetic manipulation. A differential screening for altered gene expression that correlates with changes in behavior should allow for the identification of genes whose products may be specifically involved in the therapeutic effects of antidepressant drugs. Therefore, we propose to first establish a large scale database of gene expression levels in mice, using pharmacological and genetic tools to modify their behavior in the NSF. Second, we will submit this database to a battery of bioinformatic analyses In order to extract information regarding genes, trends and patterns of altered gene expression that may correlate with the behavioral profile. Finally, we will characterize the newly identified genes, as putative new targets for antidepressant drug treatments.