title: Desipramine treatment has minimal effects on the brain accumulation of glucocorticoids in P-gp-deficient and wild-type mice.
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, 20 mg/kg/day, IP) or acute administration (20 min brain perfusion in the presence of either 0.9 μM or 10 μM 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.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK. brittany.mason@utsouthwestern.edu
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Mason
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003891:Desipramine / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000929:Antidepressive Agents, Tricyclic; D005938:Glucocorticoids; D003907:Dexamethasone; D003891:Desipramine; D003345:Corticosterone