Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight, and hippocampal glucocorticoid receptors in male C57BL/6 mice.

Abnormal hypothalamic-pituitary-adrenocortical (HPA) activity may provide clues to the neurochemistry of depression. Psychotic depression has one of the highest rates of elevated HPA activity and is most often responsive to the tricyclic class of antidepressants. Because successful treatment resolves HPA as well as psychiatric symptoms, we hypothesized, in light of evidence that tricyclic antidepressants can affect glucocorticoid receptor function, that these drugs would mimic glucocorticoid feedback inhibition of HPA activity. To test this hypothesis, we measured circadian nadir (morning) and peak (evening) as well as restraint stress-induced levels of plasma ACTH and corticosterone in adrenalectomized (ADX) and sham-ADX (Sham) male C57BL/6 mice after 8 wk of imipramine (20 mg/kg/d, ip) or saline treatment. Antidepressant efficacy was confirmed by decreased immobility in forced-swim testing. When glucocorticoids were low or absent, imipramine mimicked glucocorticoid action in inhibiting evening ACTH in ADX mice and tending to inhibit morning corticosterone in Shams. However, when glucocorticoid levels were high, imipramine appeared to interfere with feedback inhibition by increasing post-stress ACTH and tending to increase evening corticosterone in Sham mice. Imipramine also decreased thymus weight in ADX and increased thymus weight in Sham mice. Imipramine stimulated morning ACTH in ADX mice, possibly by mimicking facilitative effects of high glucocorticoids. Short-term imipramine treatment was capable of inducing nuclear translocation of hippocampal glucocorticoid receptors in ADX mice. We conclude that imipramine effects on glucocorticoid-sensitive endpoints in vivo resemble those of a glucocorticoid partial agonist.