Our group has studied the mechanisms of action of antidepressant drugs in animal models. Our approach has been to administer antidepressant drugs under a therapeutic regimen of chronic, long-term administration. This is done in normal rats or in rats subjected to stressors that are thought to model human depression. One stress model, transient immobilization, has produced data suggesting that hypothalamic neuroendocrine and brainstem noradrenergic systems are involved, specifically the corticotropin releasing hormone (CRH) and vasopressin systems of the hypothalamic paraventricular nucleus (PVN, seen in picture) and the locus coeruleus-norepinephrine system.
Clinical studies demonstrate that the efficacy of antidepressant drugs occurs typically after several weeks of treatment, so it is believed that the medication causes delayed CNS adaptations. Previous work in this lab established that long-term treatment with imipramine, fluoxetine (Prozac), and two other drugs reduces HPA axis activity with delayed onset (after 2 wks), and the changes occur at the level of gene transcription in select structures associated with the HPA axis. We also found that repeated electroconvulsive shock (ECS), a highly effective therapy for the treatment of major depression, produced enduring changes in PVN CRH and locus coeruleus tyrosine hydroxylase (TH) mRNA levels in rats. The time course of events (delayed onset, long duration) implicate CRH as a principal mediator of the antidepressant effects of antidepressant drugs and ECS. This is significant because CRH is the principal modulator of hypothalamic-pituitary-adrenal (HPA) axis activity and, consequently, it largely determines blood levels of the steroid cortisol.
Recently, we used in situ hybridization histochemistry to examine in rats the effects of short-term (2 wks) and long-term (8 wks) oral administration of St. John's wort and hypericin (an active constituent of St. John's wort) on the expression of genes that may be involved in the regulation of the HPA axis. The results showed that the natural herbiceutical compounds produced similar neurochemical changes as the synthetic prototypical drug imipramine.
Next, we compared the effects of long-term daily oral administration of imipramine or St. John's wort on changes in gene transcription induced by immobilization stress. The neurochemical alterations in stress-responsive rat brain circuits were blocked by administration of the drugs, suggesting a molecular mechanism of action of both imipramine and St. John's wort that is relevant to their therapeutic efficacy in treating certain forms of depression.
Brady, L. S., Whitfield, H. J. Jr., Fox, R. J., Gold, P. W., and Herkenham, M. Long-term imipramine administration increases mineralocorticoid receptor mRNA in the hippocampus and decreases corticotropin-releasing hormone mRNA in the hypothalamus of rats. J. Clin. Invest., 87: 831-837, 1991.
Brady, L. S., Gold, P. W., Herkenham, M., Lynn, A. B., and Whitfield, H. J. Jr. The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Research, 572: 117-125, 1992.
Brady, L. S., Lynn, A. B., Glowa, J. R., Le, D. Q., and Herkenham, M. Repeated electroconvulsive shock produces long-lasting increases in mRNA expression of corticotropin-releasing hormone and tyrosine hydroxylase in rat brain: therapeutic implications. J. Clin. Invest., 1994; 94:1263-1268.
Butterweck, V. Winterhoff, H. and Herkenham, M. St. John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats. Mol. Psychiatry, 2001; 6: 547-564.
Herkenham, M. Folliculo-stellate (FS) cells of the anterior pituitary mediate interactions between the endocrine and immune systems. Endocrinology, 146: 33-34, 2005.