title: The cytochrome P450 2D-mediated formation of serotonin from 5-methoxytryptamine in the brain in vivo: a microdialysis study.
abstract: The cytochrome P450 2D (CYP2D) mediates synthesis of serotonin from 5-methoxytryptamine (5-MT), shown in vitro for cDNA-expressed CYP2D-isoforms and liver and brain microsomes. We aimed to demonstrate this synthesis in the brain in vivo. We measured serotonin tissue content in brain regions after 5-MT injection into the raphe nuclei (Model-A), and its extracellular concentration in rat frontal cortex and striatum using an in vivo microdialysis (Model-B) in male Wistar rats. Naïve rats served as control animals. 5-MT injection into the raphe nuclei of PCPA-(tryptophan hydroxylase inhibitor)-pretreated rats increased the tissue concentration of serotonin (from 40 to 90% of the control value, respectively, in the striatum), while the CYP2D inhibitor quinine diminished serotonin level in some brain structures of those animals (Model-A). 5-MT given locally through a microdialysis probe markedly increased extracellular serotonin concentration in the frontal cortex and striatum (to 800 and 1000% of the basal level, respectively) and changed dopamine concentration (Model-B). Quinine alone had no effect on serotonin concentration; however, given jointly with 5-MT, it prevented the 5-MT-induced increase in cortical serotonin in naïve rats and in striatal serotonin in PCPA-treated animals. These results indicate that the CYP2D-catalyzed alternative pathway of serotonin synthesis from 5-MT is relevant in the brain in vivo, and set a new target for the action of psychotropics.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Haduch
authors.forename: Ewa
authors.initials: E
authors.lastname: Bromek
authors.forename: Marta
authors.initials: M
authors.lastname: Kot
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kamińska
authors.forename: Krystyna
authors.initials: K
authors.lastname: Gołembiowska
authors.forename: Wladyslawa A
authors.initials: WA
authors.lastname: Daniel
mesh_terms: D008735:5-Methoxytryptamine / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D011803:Quinine / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000096:biosynthesis*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D012701:Serotonin; D008735:5-Methoxytryptamine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D004298:Dopamine
keywords: 5-methoxytryptamine O-demethylation; CYP2D; cytochrome P450; in vivo microdialysis; rat brain structures; serotonin