Effect of metyrapone on the fluoxetine-induced change in extracellular dopamine,serotonin and their metabolites in the rat frontal cortex

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis,and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. metyrapone (an inhibitor of the enzyme 11-β-hydroxylase) has been found to be effective as an adjunctive therapy in combination with other antidepressants (ads) in both treatment-resistant depression and animal models. to understand the mechanism of the clinical efficacy of a combination of an ad and metyrapone in treatment-resistant depression,the present study was aimed at determining the influence of fluoxetine (flu; a selective serotonin re-uptake inhibitor) and metyrapone,given separately or jointly,on the extracellular level of dopamine (da),serotonin (5-ht) and their metabolites in rat frontal cortex of freely moving rats using microdialysis and high performance liquid chromatography (hplc) with electrochemical detection. flu (10 mg/kg) given alone increased the extracellular level of da and 5-ht in the rat frontal cortex. metyrapone (100 mg/kg) alone did not change the level of monoamines. acombination of flu and metyrapone produced the same change in the efflux of both daand 5-ht as did flu alone. however,the latter combination (flu and metyrapone) produced significantly bigger increases in the levels of extracellullar da metabolites (3,4-dihydroxyphenylacetic acid,homovanillic acid) and a 5-ht metabolite (5-hydroxyindoleacetic acid) than did flu alone. the above findings suggest that - among other mechanisms - increases in the levels of extracellullar da and 5-ht metabolites may play a role in the enhancement of flu efficacy by metyrapone,and may be of crucial importance to the pharmacotherapy of drug-resistant depression. copyright © 2010 by institute of pharmacology polish academy of sciences.