Norepinephrine-glucocorticoids interaction does not annul the opposite effects of the individual treatments on cellular plasticity in neuroblastoma cells.

The plasticity hypothesis of major depression states that glucocorticoids may be detrimental to neuronal plasticity while monoamines and antidepressants may reconstitute cellular plasticity. The aim of the present study was to investigate how dexamethasone, a synthetic glucocorticoid, and norepinephrine, both of which are involved in depression, interact to affect aspects of neuronal plasticity. Dexamethasone and norepinephrine administered separately oppositely affected differentiation of human neuroblastoma SH-SY5Y cells, observed by both morphological alterations and gene expression, at the level of mRNA and protein of the differentiation markers Gap-43, L1 and laminin. Norepinephrine increased differentiation, manifested as an increase in neurite length, neurite number, and gene expression, while dexamethasone reduced these parameters. Opposite effects were also observed in the expression of the transcription factor CREB with norepinephrine upregulating phosphorylated CREB (pCREB) levels, while dexamethasone downregulated CREB mRNA and protein levels, as well as pCREB levels. Interestingly, co-administration of dexamethasone and norepinephrine resulted in morphology more differentiated than control and similar to that induced by norepinephrine, albeit to a lesser degree. The alterations in the expression of the differentiation markers induced by norepinephrine or dexamethasone treatments were mostly annulled by the co-treatment. However, pCREB levels were robustly enhanced by co-treatment, as compared to both control and norepinephrine treated cells, providing a possible explanation for the morphological increase in differentiation. These results suggest that in order for cells to combat the deleterious effects of glucocorticoids, a hyperactivation of pCREB may be necessary to restore differentiation and plasticity.