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

Abstract

The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoidsFbut this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region ( + 31%; p ¼ 0.045); in contrast, in abcb1ab (À/À) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (À45%; p ¼ 0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (À/À) mice, but in abcb1ab (À/À) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (À/À) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (À39%; p ¼ 0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (À9 to À23%), but had no effect on 11b-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.

Effects of acute or 3-day treatments of Hypericum caprifoliatum Cham. & Schltdt. (Guttiferae) extract or of two established antidepressants on basal and stress-induced increase in serum and brain corticosterone levels

“…Recent works suggest a possible role of membrane steroid transporters, like MDR-Pgp, in the regulation of glucocorticoids receptors function during antidepressant treatment (Juruena et al, 2004;Pariante et al, 2004;Pariante, 2006;Yau et al, 2007). Therefore, by inhibiting MDR-Pgp in vivo, antidepressants could directly increase the access of corticosterone to the brain, enhance GR-mediated negative feedback by endogenous glucocorticoids on the HPA axis and thus reduce HPA-axis activity .…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Administration of the antidepressant desipramine for 7 days induces mRNA expression of the glucocorticoid receptor in the brains of wild-type, but not Mdr1a-null mice (Yau et al, 2007). Induction of the glucocorticoid receptor corresponds with a decrease in corticosterone levels in desipramine-treated wild-type mice (Yau et al, 2007). From these findings, the authors suggest that Pgp is a molecular target of antidepressant regulation of the hypothalamic-pituitary-adrenal axis (Yau et al, 2007).…”

“…Induction of the glucocorticoid receptor corresponds with a decrease in corticosterone levels in desipramine-treated wild-type mice (Yau et al, 2007). From these findings, the authors suggest that Pgp is a molecular target of antidepressant regulation of the hypothalamic-pituitary-adrenal axis (Yau et al, 2007).…”

“…It is thought that antidepressants inhibit Pgp activity and in turn enhance glucocorticoid receptor function (Pariante et al, 2001(Pariante et al, , 2003. Administration of the antidepressant desipramine for 7 days induces mRNA expression of the glucocorticoid receptor in the brains of wild-type, but not Mdr1a-null mice (Yau et al, 2007). Induction of the glucocorticoid receptor corresponds with a decrease in corticosterone levels in desipramine-treated wild-type mice (Yau et al, 2007).…”

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

“…It is noteworthy that this membrane transporter has been proposed as a promising therapeutic target for treatment of depression and the presumed steroid resistance in this disease (Pariante, 2008). For instance, the antidepressant desipramine requires the mdr1a P-glycoprotein to up-regulate GRs in the mouse brain (Yau et al, 2007), potentially normalizing HPA-axis function, which is often aberrant in depressives. Genetic polymorphisms in the mdr1a P-glycoprotein were found to predict clinical response to antidepressants (Pariante, 2008).…”