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Dexamethasone in the presence of desipramine enhances MAPK/ERK1/2 signaling possibly via its interference with β-arrestin

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Antidepressant medication is the standard treatment for major depression disorder (MDD). However, the response to these treatments is often incomplete and many patients remain refractory. In the present study, we show that the glucocorticoid receptor (GR) agonist dexamethasone (DEX) increased MAPK/ERK1/2 signaling in the presence of the noradrenergic antidepressant, desipramine (DMI), while no such effect was induced by DEX or DMI alone in human neuroblastoma SH-SY5Y cells. This enhancement was dependent on the activation of both α2 adrenergic receptors (AR) and GR. The timing of MAPK/ERK1/2 activation as well as DEX-induced reduction in membranous α2 AR suggests the involvement of a β-arrestin-dependent mechanism. In line with the latter, DEX increased cytosolic and decreased membranous levels of β-arrestin. Concomitantly, DEX induced a time-dependent increase in cytosolic α2 AR-β-arrestin interaction and a decrease in β-arrestin interaction with Mdm2 E3 ubiquitin ligase. All of these effects of DEX were prevented by the GR antagonist RU486. Our data suggest an additional intracellular role for DEX, in which activation of GR interferes with the trafficking and degradation of β-arrestin-α2c-AR complex. We suggest that such an interaction in the presence of DMI can enhance MAPK/ERK1/2 signaling, a key player in neural plasticity and neurogenesis processes, which is impaired in MDD, while stimulated by antidepressants.

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Acknowledgments

This study was supported by a grant of the Chief Scientist of the Israeli Ministry of Health. Mdm2 antibodies were obtained as a gift from Prof. A. Ciechanover, Technion IIT, Israel.

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  1. Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine and B. Rappaport Research Institute, Technion IIT, POB 9649, 31096, Haifa, Israel

    Anat Lucki, Ehud Klein, Rachel Karry & Dorit Ben-Shachar

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  1. Anat Lucki
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  4. Dorit Ben-Shachar
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Correspondence to Dorit Ben-Shachar.

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Lucki, A., Klein, E., Karry, R. et al. Dexamethasone in the presence of desipramine enhances MAPK/ERK1/2 signaling possibly via its interference with β-arrestin. J Neural Transm 121, 289–298 (2014). https://doi.org/10.1007/s00702-013-1099-5

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  • DOI: https://doi.org/10.1007/s00702-013-1099-5

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