ABCB1 (MDR1)-Type P-Glycoproteins at the Blood–Brain Barrier Modulate the Activity of the Hypothalamic–Pituitary–Adrenocortical System: Implications for Affective Disorder

Abstract

Multidrug-resistance gene 1-type P-glycoproteins (ABCB1-type P-gps) protect the brain against the accumulation of many toxic xenobiotics and drugs. We recently could show that the access of the endogenous glucocorticoids corticosterone and cortisol to the brain are regulated by ABCB1-type P-gps in vivo. ABCB1-type P-gp function, therefore, is likely to exert a profound influence on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Hyperactivity of the HPA system is frequently observed in human affective disorder, and a considerable amount of evidence has been accumulated suggesting that normalization of the HPA system might be the final step necessary for stable remission of the disease. To examine whether blood-brain barrier (BBB) function influences neuroendocrine regulation, we investigated HPA system activity in abcb1ab (À/À) mice under basal conditions and following stress. Abcb1ab (À/À) mice showed consistently lower plasma ACTH levels and lower evening plasma corticosterone levels. CRH mRNA expression in the hypothalamic paraventricular nucleus was decreased and pituitary POMC mRNA expressing cells were significantly reduced in number in abcb1ab (À/À) mutants; however, they showed a normal activation of the HPA system following CRH stimulation. Lower doses of dexamethasone were required to suppress plasma corticosterone levels in mutants. Our data thus provide evidence for a sustained suppression of the HPA system at the hypothalamic level in abcb1ab (À/À) mice, suggesting that BBB function significantly regulates HPA system activity. Whether naturally occurring polymorphisms in the human ABCB1 gene might result in persistent changes in the responsiveness and regulation of the HPA system will be the subject of future investigations, correlating both genetic information with individual characteristics of the neuroendocrine phenotype.

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

“…Moreover, we find that desipramine reduces MDR PGP (Mdr1a) expression in the hippocampus of FVB/N control controls, again consistent with previous work in cell lines (Varga et al, 1996;Szabo et al, 1999;Weiss et al, 2003;Pariante et al, 2003b;Weber et al, 2005). Finally, we replicate the previous finding by Muller et al (2003) showing that abcb1ab (À/À) mice have lower corticosterone levels than FVB/N controls. Indeed, desipramine treatment (in our model, a pharmacological 'knockdown' of MDR PGP) also lowers plasma corticosterone levels in controls, to levels indistinguishable from abcb1ab (À/À) mice.…”

“…Post hoc analyses showed that untreated abcb1ab (À/À) mice had lower corticosterone levels than untreated FVB/N mice (gray column on the right vs gray column on the left; p ¼ 0.02); this replicates the findings by Muller et al (2003). It is also of note that there was an increase of corticosterone levels in saline-treated abcb1ab (À/À) mice compared with untreated abcb1ab (À/À) mice (gray vs white columns on the right; p ¼ 0.053), whereas the same phenomenon did not occur in FVB/N controls (gray vs white columns on the left; p ¼ 0.7).…”

“…However, measuring endogenous corticosterone in the brain may not be appropriate to address this issue, because antidepressant-induced changes in plasma corticosterone would alter the levels in the brain and, hence, confound any inference on BBB permeability (Carroll et al, 1975). Measuring the access to the brain of radioactive glucocorticoids administered in the periphery (Meijer et al, 1998;Karssen et al, 2001Karssen et al, 2002Muller et al, 2003), or through brain perfusion (Pariante et al, 2004b), are more appropriate techniques to answer this kind of question. Moreover, these authors administered amitriptyline 10 mg/ kg/d, a dose that may be too low to affect the HPA axis in mice.…”

“…The abcb1ab (À/À) mice have been previously shown to have increased access of corticosterone to the brain and a more effective HPA axis negative feedback because of the facilitated entry of endogenous and exogenous glucocorticoids to the brain (Uhr et al, 2002;Muller et al, 2003). Our hypothesis is that antidepressants increase GR expression and decrease HPA axis activity by modulating MDR PGP; and therefore that these effects of antidepressants would not be present in the abcb1ab (À/À) mice.…”

“…Glucocorticoids are excreted from fibroblasts, leukocytes, and epithelial cells by the ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) present in two isoforms in rodents (abcb1a and abcb1b) and one isoform only in humans (ABCB1). Interestingly, the MDR PGP is also localized at the luminal membrane of the endothelial cells of the blood-brain barrier (BBB), and limits the access of endogenous glucocorticoids to the mouse and human brain Meijer et al, 1998;Karssen et al, 2001Karssen et al, , 2002Uhr et al, 2002;Muller et al, 2003). We have found that antidepressants enhance GR function in mouse fibroblast cells by inhibiting the MDR PGP, and thus increasing intracellular concentrations of glucocorticoids (Pariante et al, 2001(Pariante et al, , 2003a; a similar effect is also present in rat cortical neurones (Pariante et al, 2003a).…”