St John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term andlong-term administration in normal and stressed rats

Clinical studies demonstrate that the antidepressant efficacy of St John's wort (Hypericum) is comparable to that of tricyclic antidepressants such as imipramine. Onset of efficacy of these drugs occurs after several weeks of treatment. Therefore, we used in situ hybridization histochemistry to exam ine in rats the effects of short-term (2 weeks) and long-term (8 weeks) adm inistration of imipramine, Hypericum extract, and hypericin (an active cons tituent of St John's wort) on the expression of genes that may be involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Imipram ine (15 mg kg(-1)), Hypericum (500 mg kg(-1)), and hypericin (0.2 mg kg(-1) ) given daily by gavage for 8 weeks but not for 2 weeks significantly decre ased levels of corticotropin-releasing hormone (CRH) mRNA by 16-22% in the hypothalamic paraventricular nucleus (PVN) and serotonin 5-HT1A receptor mR NA by 11-17% in the hippocampus. Only imipramine decreased tyrosine hydroxy lase (TH) mRNA levels in the locus coeruleus (by 23%), and only at 8 weeks. The similar delayed effects of the three compounds on gene transcription s uggests a shared action on the centers that control HPA axis activity. A se cond study was performed to assess the effects of long-term imipramine and Hypericum administration on stress-induced changes in gene transcription in stress-responsive circuits. Repeated immobilization stress (2 h daily for 7 days) increased mRNA levels of CRH in the PVN, proopiomelanocortin (POMC) in the anterior pituitary, glutamic acid decarboxylase (GAD 65/67) in the bed nucleus of the stria terminalis (BST), cyclic AMP response element bind ing protein (CREB) in the hippocampus, and TH in the locus coeruleus. It de creased mRNA levels of 5-HT1A and brain-derived neurotrophic factor (BDNF) in the hippocampus. Long-term pretreatment with either imipramine or Hyperi cum reduced to control levels the stress-induced increases in gene transcri ption of GAD in the BST, CREB in the hippocampus, and POMC in the pituitary . The stress-induced increases in mRNA levels of CRH in the PVN and TH in t he locus coeruleus were reduced by imipramine but not by Hypericum. The str ess-induced decreases in BDNF and 5-HT1A mRNA levels were not prevented by either drug. Taken together, these data show: (1) that Hypericum and hyperi cin have delayed effects on HPA axis control centers similar to those of im ipramine; and (2) that select stress-induced changes in gene transcription in particular brain areas can be prevented by long-term treatment with eith er the prototypic tricyclic antidepressant imipramine or the herbiceutical St John's wort. However, imipramine appears to be more effective in blockin g stress effects on the HPA axis than the plant extract.