Elucidating the neural mechanisms of the antidepressant response using mouse models

 The therapeutic effects of antidepressants require several weeks of treatment to emerge. We have developed novel animal models in which mice exhibit behavioral responses to chronic, but not subchronic, treatment with antidepressants. We used these models to investigate the mechanisms by which chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine reduces anxiety- and depression-related behavior in mice. We examined a potential role for 5-HT1A receptors and hippocampal neurogenesis in the behavioral response to chronic fluoxetine using 5-HT1A knockout mice and x-irradiation of hippocampal progenitor cells. Results showed that the 5-HT1A receptor was required for the behavioral response to acute, but not chronic, fluoxetine treatment. Furthermore, ablation of progenitor cells in the hippocampus via x-irradiation did not alter the behavioral response to chronic fluoxetine. Our findings suggest that the behavioral effects of chronic SSRI treatment do not depend on 5-HT1A receptor activation or increases in hippocampal neurogenesis.

08/015/07