Abstract
Despite widespread use of antidepressants, the factors underlying the behavioral response to antidepressants are unknown. It has been shown that antidepressant treatment promotes the proliferation and survival of neurons in the adult hippocampus via enhanced serotonergic signaling, but it is unclear whether hippocampal neurogenesis is responsible for the behavioral response to antidepressants. Furthermore, a large subpopulation of patients fails to respond to antidepressant treatment due to presumed underlying genetic factors. In the present study, we have used the phenotypic and genotypic variability of inbred mouse strains to show that there is a genetic component to both the behavioral and neuronal effects of chronic fluoxetine treatment, and that this antidepressant induces an increase in hippocampal cell proliferation only in the strains that also show a positive behavioral response to treatment. Furthermore, the behavioral and neuronal responses are associated with an upregulation of genes known to promote neuronal proliferation and survival. These results suggest that inherent genetic predisposition to increased serotonin-induced neurogenesis may be a determinant of antidepressant efficacy.
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Acknowledgements
We thank Brandon Young and Bradley Long for invaluable work in producing the microarray data (Genomics Core, Scripps Florida), Paul Kenny (Scripps Florida), and Tim Wiltshire (Genomic Institute of the Novartis Research Foundation) for their thoughtful comments and suggestions, and Gerd Kempermann (Max Delbrück Center for Molecular Medicine) for consultation and advice regarding BrdU labeling. This study was supported by a grant from the state of Florida.
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Miller, B., Schultz, L., Gulati, A. et al. Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine. Neuropsychopharmacol 33, 1312–1322 (2008). https://doi.org/10.1038/sj.npp.1301497
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