title: 5-hydroxy-3-ethylamino-2-oxindole is not formed in rat brain following a neurotoxic dose of methamphetamine: evidence that methamphetamine does not induce the hydroxyl radical-mediated oxidation of serotonin.
abstract: Oxygen radicals have been implicated in the neurodegenerative and other neurobiological effects evoked by methamphetamine (MA) in the brain. It has been reported that shortly after a single large subcutaneous dose of MA to the rat, the serotonergic neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) is formed in the cortex and hippocampus. This somewhat controversial finding suggests that MA potentiates formation of the hydroxyl radical (HO.) that oxidizes 5-hydroxytryptamine (5-HT) to 5,6-DHT, which, in turn, mediates the degeneration of serotonergic terminals. A major and more stable product of the in vitro HO.-mediated oxidation of 5-HT is 5-hydroxy-3-ethylamino-2-oxindole (5-HEO). In this investigation, a method based on HPLC with electrochemical detection (HPLC-EC) has been developed that permits measurement of very low levels of 5-HEO in rat brain tissue in the presence of biogenic amine neurotransmitters/metabolites. After intracerebroventricular administration into rat brain, 5-HEO is transformed into a single major, but unknown, metabolite that can be detected by HPLC-EC. One hour after administration of MA (100 mg/kg s.c.) to the rat, massive decrements of 5-HT were observed in all regions of the brain examined (cortex, hippocampus, medulla and pons, midbrain, and striatum). However, 5-HEO, its unidentified metabolite, or 5,6-DHT were not detected as in vivo metabolites of 5-HT. MA administration, in particular to rats pretreated with pargyline, resulted in the formation of low levels of N-acetyl-5-hydroxytryptamine (NAc-5-HT) in all brain regions examined. These results suggest that MA does not potentiate the HO.-mediated oxidation of 5-HT. Furthermore, the rapid MA-induced decrease of 5-HT might not only be related to oxidative deactivation of tryptophan hydroxylase, as demonstrated by other investigators, but also to the inhibition of tetrahydrobiopterin biosynthesis by NAc-5-HT. The massive decrements of 5-HT evoked by MA are accompanied by small or no corresponding increases in 5-hydroxyindole-3-acetic acid (5-HIAA) levels. This is due, in part, to the relatively rapid clearance of 5-HIAA from the brain and monoamine oxidase (MAO) inhibition by MA. However, the loss of 5-HT without corresponding increases in its metabolites point to other mechanisms that might deplete the neurotransmitter, such as oxidation by superoxide radical anion (O2.-), a reaction that in vitro does not generate 5-HEO or 5,6-DHT but rather another putative neurotoxin, tryptamine-4,5-dione. One hour after administration, MA evokes large depletions of norepinephrine (NE) throughout the brain but somewhat smaller decrements of dopamine (DA) that are restricted to the nigrostriatal pathway. Furthermore, MA evokes a major shift in the metabolism of both NE and DA from the pathway mediated by MAO to that mediated by catechol-O-methyltransferase. The profound and widespread effects of MA on the noradrenergic system, but more anatomically localized influence on the dopaminergic system, suggests that NE in addition to DA, or unusual metabolites of these neurotransmitters, might play roles in the neurodegenerative effects evoked by this drug.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, U.S.A.
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: M Z
authors.initials: MZ
authors.lastname: Wrona
authors.forename: G
authors.initials: G
authors.lastname: Dryhurst
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017665:Hydroxyl Radical / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D000078183:Oxindoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: C105575:5-hydroxy-3-ethylamino-2-oxindole; D015259:Dopamine Agents; D007211:Indoles; D000078183:Oxindoles; D012701:Serotonin; D017665:Hydroxyl Radical; D008694:Methamphetamine; C006389:N-acetylserotonin