PENETRATION OF DEXAMETHASONE INTO BRAIN GLUCOCORTICOID TARGETS IS ENHANCED IN MDR1A P-GLYCOPROTEIN KNOCKOUT MICE

Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-trans porting P-glycoprotein product from the blood-brain barrier on the dis tribution and cell nuclear uptake of [H-3]-dexamethasone in the brain. [H-3]-dexamethasone (4 mu g/kg mouse) was administered sc to adrenale ctomized mdr1a (-/-) and mdr1a (+/+) mice. One hour later, the mice we re decapitated, and the radioactivity was measured in homogenates of c erebellum, blood, and liver following extraction of the radioactive st eroid. The frontal brain was cut in sections for autoradiography. In t he cerebellum of the mdr1a mutants, the amount of [H-3]-dexamethasone relative to blood was about 5-fold higher than observed in the control s, whereas the ratio in blood vs. liver was not different. Using autor adiography, it was found that brain areas expressing the glucocorticoi d receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in c ell nuclear uptake of radiolabeled steroid. The amount of retained ste roid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [H-3]-dexamethasone concentration in pi tuitary was not affected by mdr1a gene disruption. The GR messenger RN A expression pattern in hippocampus was not different between the wild types and mdr1a mutants, which rules out altered receptor expression as a cause of the enhanced dexamethasone uptake. In conclusion, the pr esent study demonstrates that the brain is resistant to penetration by dexamethasone because of mdr1a activity at the level of the blood-bra in barrier. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release. Dexameth asone poorly substitutes for depletion of the endogenous glucocorticoi d from the brain and therefore, in this tissue, may cause a condition resembling that of adrenalectomy.