title: Non-invasive stress-free application of glucocorticoid ligands in mice.
abstract: Most drug delivery procedures induce stress, which might interfere with the pharmacological action of the drug and behaviour. Stress is deduced from high and long-lasting elevations of the hormone corticosterone. We set out to develop a non-invasive, stress-free method of drug delivery in mice. Validation consisted of delivery of glucocorticoid ligands via oats to male C57BL/6J mice. Oat consumption induced a small increase in corticosterone concentrations after 15 min (<50 ng/ml) that returned to low resting levels at t=30 (<10 ng/ml). Gavage and intraperitoneal (i.p.) vehicle injections resulted in long-lasting corticosterone elevations (>100 ng/ml at t=30 and approximately 50 ng/ml at t=60 min after delivery). Adding corticosterone to oats resulted in threefold higher plasma corticosterone in the 15.0-mg/kg group (+/-250 ng/ml) compared to the 4.5-mg/kg group at t=30 and 90. Application of the glucocorticoid receptor antagonist RU38486 (200 mg/kg) elevated plasma corticosterone for at least 8h. Additional swimming increased corticosterone even further. Presumably, already the small oat-consumption-induced increase of corticosterone requires negative feedback via glucocorticoid receptors. In conclusion, the context-dependent and dose-controlled application of drugs via oats avoids confounding strong stress system activation and makes it suitable for studies on learning and memory processes.
authors.affiliation: Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands. s.dalm@lacdr.leidenuniv.nl
authors.forename: Sergiu
authors.initials: S
authors.lastname: Dalm
authors.forename: Vera
authors.initials: V
authors.lastname: Brinks
authors.forename: Maaike H
authors.initials: MH
authors.lastname: van der Mark
authors.forename: E Ron
authors.initials: ER
authors.lastname: de Kloet
authors.forename: Melly S
authors.initials: MS
authors.lastname: Oitzl
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D018554:Avena; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013315:Stress, Psychological / Q000503:physiopathology
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D006727:Hormone Antagonists; D008024:Ligands; D014677:Pharmaceutical Vehicles; D011965:Receptors, Glucocorticoid; D015735:Mifepristone