TY - JOUR
T1 - Desipramine treatment has minimal effects on the brain accumulation of glucocorticoids in P-gp-deficient and wild-type mice
AU - Mason, Brittany L.
AU - Thomas, Sarah A.
AU - Lightman, Stafford L.
AU - Pariante, Carmine M.
N1 - Funding Information:
This work was supported by a UK Medical Research Council (MRC) Clinician Scientist Fellowship to C.M. Pariante ( G108/603 ), and was supported by the Wellcome Trust [080268], granted to S.A. Thomas. Neither funding source had any further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
KW - Antidepressants
KW - Blood-brain barrier
KW - Desipramine
KW - Glucocorticoids
KW - Hypothalamic-pituitary-adrenal (HPA) axis
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U2 - 10.1016/j.psyneuen.2011.03.008
DO - 10.1016/j.psyneuen.2011.03.008
M3 - Article
C2 - 21481537
AN - SCOPUS:80052731723
SN - 0306-4530
VL - 36
SP - 1351
EP - 1360
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
IS - 9
ER -