Effect of metyrapone on the fluoxetine-induced change in extracellular dopamine, serotonin and their metabolites in the rat frontal cortex.
Journal Title: Pharmacological Reports - Year 2010, Vol 62, Issue 6
Abstract
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 reuptake 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 DA and 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.
Authors and Affiliations
Zofia Rogóż, Krystyna Gołembiowska
Keywords
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