Desipramine treatment has minimal effects on the brain accumulation of glucocorticoids in P-gp-deficient and wild-type mice

Brittany L. Mason, Sarah A. Thomas, Stafford L. Lightman, Carmine M. Pariante

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with depression can be reduced by antidepressants, which are thought to improve endogenous glucocorticoid-mediated negative feedback. A proportion of peripherally released glucocorticoids need to enter brain tissue, protected by the blood-brain barrier (BBB), in order to achieve this negative feedback effect at the level of the central nervous systems (CNS). The multidrug resistance transporter P-glycoprotein (P-gp) has been shown to actively transport glucocorticoid hormones and has been implicated in the regulation of glucocorticoid access to the CNS. Using an in situ brain/choroid plexus perfusion method, we tested the hypothesis that the antidepressant desipramine increases glucocorticoid accumulation in the mouse brain by inhibiting P-gp, following either chronic treatment (8 days, 20mg/kg/day, IP) or acute administration (20min brain perfusion in the presence of either 0.9μM or 10μM desipramine). Contrary to our hypothesis, chronic treatment with desipramine did not affect the accumulation of [ 3H]dexamethasone in any sample compared to saline-treated mice. Acute desipramine had limited and variable effects on glucocorticoid accumulation in the CNS, with accumulation of [ 3H]dexamethasone increased in the cerebellum, accumulation of [ 3H]cortisol reduced in the frontal cortex, hypothalamus, and cerebellum, and accumulation of [ 3H]corticosterone (the endogenous glucocorticoid in rodents) not affected. Overall, under the conditions tested, these results do not support the hypothesis that treatment with desipramine can inhibit P-gp at the BBB and subsequently increase the accumulation of glucocorticoids in the brain.

Original languageEnglish (US)
Pages (from-to)1351-1360
Number of pages10
JournalPsychoneuroendocrinology
Volume36
Issue number9
DOIs
Publication statusPublished - Oct 1 2011

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Keywords

  • Antidepressants
  • Blood-brain barrier
  • Desipramine
  • Glucocorticoids
  • Hypothalamic-pituitary-adrenal (HPA) axis

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Endocrine and Autonomic Systems

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