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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    ABSTRACT: Major depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus-pituitary-adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan(®) SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR)=0.360, 95% confidence interval [CI]: [0.140-0.950], p=0.022; C3435T: OR=0.306, 95% CI: [0.096-0.980], p=0.042; and G2677TA: OR=0.300, 95% CI: [0.100-0.870], p=0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR=0.313, 95% CI: [0.118-0.832], p=0.016, FDR p=0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.
    Genetic Testing and Molecular Biomarkers 11/2013; 18(1). DOI:10.1089/gtmb.2013.0197 · 1.46 Impact Factor
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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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    ABSTRACT: The main purpose of this study was to evaluate the effect of aging on plasma and free corticosterone (CORT) levels in the brain in basal conditions and in response to an acute stressor. Microdialysis experiments were performed in the hippocampus (HC) and the prefrontal cortex (PFC) of young adult (6 months) and aged (24 months) male Wistar rats. Basal free levels of CORT in the HC and the PFC were higher in aged animals. Restraint stress increased plasma CORT and free CORT levels in the HC and the PFC both in young and aged animals. However, while the increase of plasma CORT was higher in aged rats compared with young rats, the increases of free CORT in the HC and the PFC were not different between these two groups of rats. These results suggest that the changes produced by aging in the brain may be related to the enhanced basal levels of free CORT and not to the CORT increases in response to stress.
    Neurobiology of aging 02/2012; 33(2):375-82. DOI:10.1016/j.neurobiolaging.2010.02.015 · 5.01 Impact Factor
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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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    ABSTRACT: To investigate neurobiological correlates of trait anxiety, CD1 mice were selectively bred for extremes in anxiety-related behavior, with high (HAB) and low (LAB) anxiety-related behavior mice additionally differing in behavioral tests reflecting depression-like behavior. In this study, microarray analysis, in situ hybridization, quantitative real-time PCR and immunohistochemistry revealed decreased expression of the vasopressin gene (Avp) in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei of adult LAB mice compared to HAB, NAB (normal anxiety-related behavior) and HABxLAB F1 intercross controls, without detecting differences in receptor expression or density. By sequencing the regions 2.5 kbp up- and downstream of the Avp gene locus, we could identify several polymorphic loci, differing between the HAB and LAB lines. In the gene promoter, a deletion of twelve bp Delta(-2180-2191) is particularly likely to contribute to the reduced Avp expression detected in LAB animals under basal conditions. Indeed, allele-specific transcription analysis of F1 animals revealed a hypomorphic LAB-specific Avp allele with a reduced transcription rate by 75% compared to the HAB-specific allele, thus explaining line-specific Avp expression profiles and phenotypic features. Accordingly, intra-PVN Avp mRNA levels were found to correlate with anxiety-related and depression-like behaviors. In addition to this correlative evidence, a significant, though moderate, genotype/phenotype association was demonstrated in 258 male mice of a freely-segregating F2 panel, suggesting a causal contribution of the Avp promoter deletion to anxiety-related behavior. Thus, the identification of polymorphisms in the Avp gene promoter explains gene expression differences in association with the observed phenotype, thus further strengthening the concept of the critical involvement of centrally released AVP in trait anxiety.
    PLoS ONE 02/2009; 4(4):e5129. DOI:10.1371/journal.pone.0005129 · 3.23 Impact Factor
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