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

Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Neuropsychopharmacology (Impact Factor: 7.05). 12/2003; 28(11):1991-9. DOI: 10.1038/sj.npp.1300257
Source: PubMed


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 (-/-) mice under basal conditions and following stress. Abcb1ab (-/-) 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 (-/-) 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 (-/-) 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.

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    • "n vivo studies using abcb1ab ( - / - ) mice mu - tants prove that the absence of P - GP leads to an increased penetration of corticosteroid hormones in the central nervous system , which in turn , enhanced central negative feedback inhibition of stress hormone secretion , with lower plasma ACTH levels in both at basal and under stress conditions ( Muller et al . , 2003 ) . Moreover , antidepressants have also in - hibited P - GP in vitro , and decreased the HPA axis activity in vivo , leading to the hypothesis that antidepressants inhibit P - GP at the BBB and increase glucocorticoid access to the brain ( Yau et al . , 2007 ) . The gender - specific trait of our results can be explained by the differe"
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    • "However, because this is an intracellular mechanism it does not seem to have a major impact in our results using the microdialysis technique. Third, despite the lypophilic nature of CORT molecule, MDR1 type P-glycoproteins expressed in the blood brain barrier are able to actively transport different substrates against a concentration gradient such as the synthetic glucocorticoid dexamethasone , and the endogenous glucocorticoids cortisol and CORT (Meijer et al., 1998; Müller et al., 2003; Uhr et al., 2002; Wolf and Horwitz, 1992; but see Mason et al., 2008). Moreover, endogenous glucocorticoids enhance in vitro the mdr1b gene expression (Altuvia et al., 1993). "
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    • "Brains were sectioned into 14 µm slices with a cryostat (Microm HM 500, Microm, Walldorf, Germany). Three sets of sections at PVN level were taken and used for Avp or Oxytocin (Oxt) in situ hybridization (ISH) according to established protocols [20], [34]. "
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