Abstract
Dexamethasone poorly penetrates in brain. A tracer amount of [3HJ-dexamethasone administered to adrenaleetomized rats or mice is poorly retained by glucocorticoid receptors in brain, while pituitary corticotrophs containing equivalent amounts of these receptors accumulate and retain large amounts of this synthetic steroid. However, adrenaleetomized mice with a genetic disruption of the multiple drug resistance (mrdla) gene have a tenfold increase of L3H]-dexamethasone uptake in brain glucocorticoid target sites reaching levels observed in the pituitary. These data demonstrate that dexamethasone is extruded from brain by the mrd 1 a-encoded P-glycoproteins. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release, which implies that chronic dexamethasone treatment does not replace the endogenous corticosteroids depleted from brain mineralocorticoid (MRs) and glucocorticoid receptors (GRs). Dexamethasone, therefore, causes a profound disturbance in the balance of these two receptor types in hippocampus, which is an unfavourable condition threatening the neuronal integrity of this brain structure through the expression of noxious genes.
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