title: Effect of metyrapone on the fluoxetine-induced change in extracellular dopamine, serotonin and their metabolites in the rat frontal cortex.
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. A combination 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 extracellular 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 extracellular 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.affiliation: Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. rogoz@if-pan.krakow.pl
authors.forename: Zofia
authors.initials: Z
authors.lastname: Rogóż
authors.forename: Krystyna
authors.initials: K
authors.lastname: Gołembiowska
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008797:Metyrapone / Q000378:metabolism / Q000494:pharmacology*; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D000963:Antimetabolites; D008024:Ligands; C525454:N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013844:Thiazoles; D013876:Thiophenes; D014363:Tryptamines; C097216:serotonin 6 receptor; D005473:Fluoxetine; D012701:Serotonin; C117443:SB 271046; D004298:Dopamine; D008797:Metyrapone