Abstract
Although numerous studies have investigated the mechanisms underlying the fast and sustained antidepressant-like effects of ketamine, the contribution of the glucocorticoid receptor (GR) and dendritic branching remodeling to its responses remain to be fully established. This study investigated the ability of a single administration of ketamine to modulate the GR and dendritic branching remodeling and complexity in the hippocampus of mice subjected to chronic corticosterone (CORT) administration. CORT was administered for 21 days, followed by a single administration of ketamine (1 mg ∕kg, i.p.) or fluoxetine (10 mg ∕kg, p.o., conventional antidepressant) in mice. On 22nd, 24 h after the treatments, GR immunocontent in the hippocampus was analyzed by western blotting, while the dendritic arborization and dendrite length in the ventral and dorsal dentate gyrus (DG) of the hippocampus was analyzed by Sholl analysis. Chronic CORT administration downregulated hippocampal GR immunocontent, but this alteration was completely reversed by a single administration of ketamine, but not fluoxetine. Moreover, CORT administration significantly decreased dendritic branching in the dorsal and ventral DG areas and caused a mild decrease in dendrite length in both regions. Ketamine, but not fluoxetine, reversed CORT-induced dendritic branching loss in the ventral and dorsal DG areas, regions associated with mood regulation and cognitive functions, respectively. This study provides novel evidence that a single administration of ketamine, but not fluoxetine, rescued the impairments on GR and dendritic branching in the hippocampus of mice subjected to chronic CORT administration, effects that may be associated with its rapid antidepressant response.
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Acknowledgments
The authors thank funding agencies CNPq and CAPES by the financial support, and the Laboratório Multiusuário de Estudos em Biologia (LAMEB) by technical support.
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This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #310113/2017–2), and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). JB, PSB, and ALSR are CNPq Research Fellows.
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Ana Lúcia S. Rodrigues and Daiane B. Fraga designed the study and wrote the protocol. Daiane B. Fraga, Gislaine Olescowicz, Dayane Azevedo, Francielle Mina, Patricia S. Brocardo, Josiane Budni, and Anderson Camargo performed the neurochemical and morphological analyses. Daiane B. Fraga and Anderson Camargo undertook the statistical analysis. All authors wrote the first draft of the manuscript, as well as approved the final manuscript.
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Fraga, D.B., Camargo, A., Olescowicz, G. et al. Ketamine, but not fluoxetine, rapidly rescues corticosterone-induced impairments on glucocorticoid receptor and dendritic branching in the hippocampus of mice. Metab Brain Dis 36, 2223–2233 (2021). https://doi.org/10.1007/s11011-021-00743-2
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DOI: https://doi.org/10.1007/s11011-021-00743-2