Non-invasive stress-free application of glucocorticoid ligands in mice

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 ∼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 8 h. 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.