title: Effects of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in rats subjected to the forced swim test.
abstract: Major depression is frequently associated with hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in male Wistar rats subjected to the forced swim test. Metyrapone alone (50 mg/kg, but not 25 mg/kg) reduced the immobility time of rats in the forced swim test; moreover, both doses tested (25 and 50 mg/kg), dose-dependently decreased the stress-induced plasma corticosterone concentration. Joint administration of fluoxetine or tianeptine (10 mg/kg) and metyrapone (25 mg/kg - a dose inactive per se) exhibited antidepressant-like activity in the forced swim test in rats. WAY 100636 (a 5-HT(1A) antagonist), but not prazosin (an alpha(1)-adrenergic antagonist), used in doses ineffective in the forced swim test, inhibited the antidepressant-like effect induced by co-administration of fluoxetine or tianeptine with metyrapone (25 mg/kg). Combined treatment of fluoxetine or tianeptine and metyrapone inhibited stress-induced corticosterone secretion to a similar extent as metyrapone alone. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of fluoxetine or tianeptine and that, among other mechanisms, 5-HT(1A) receptors may play some role in this effect. Moreover, metyrapone exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration. These findings suggest that the co-administration of metyrapone and an antidepressant drug may be useful for the treatment of drug-resistant depression and/or depression associated with a high cortisol level.
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. rogoz@if-pan.krakow.pl
authors.forename: Zofia
authors.initials: Z
authors.lastname: Rogóz
authors.forename: Grazyna
authors.initials: G
authors.lastname: Skuza
authors.forename: Monika
authors.initials: M
authors.lastname: Leśkiewicz
authors.forename: Bogusława
authors.initials: B
authors.lastname: Budziszewska
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D003345:Corticosterone / Q000097:blood*; D003863:Depression / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000008:administration & dosage*; D008297:Male; D008797:Metyrapone / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D013550:Swimming; D013841:Thiazepines / Q000008:administration & dosage*
chemical_list: D000928:Antidepressive Agents; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013841:Thiazepines; D005473:Fluoxetine; C050504:tianeptine; D044282:Receptor, Serotonin, 5-HT1A; D003345:Corticosterone; D008797:Metyrapone