Neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) : role of endogenous dopamine and oxidative damage in the immediate and longterm inactivation of rat central tryptophan hydroxylase

Update Item Information
Title Neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) : role of endogenous dopamine and oxidative damage in the immediate and longterm inactivation of rat central tryptophan hydroxylase
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Stone, Donna Marie
Date 1988-12
Description In the rat, a single systemic injection (10 mg/kg) of the ring-substituted amphetamine analog 3,4-methylenedioxymethamphetamine (MDMA) caused rapid (within 1 h) and prolonged (up to 2 weeks) reductions in the activity of central tryptophan hydroxylase (TPH), the rate-limiting enzyme for serotonin biosynthesis. The loss of enzymatic activity was followed by a comparable decrease in central 5-hydroxyindole content. Neurochemical indices of neostriatal dopaminergic function were transiently altered by acute MDMA, but had returned to control values by 24 h. Repeated MDMA injection resulted in a loss of regional brain serotonergic parameters for up to 110 days indicative of serotonergic nerve terminal degeneration. The striatal TPH deficit remaining 3 days after MDMA administration could be prevented by prior depletion of endogenous dopamine with either $/alpha$-methyl-p-tryrosine or reserpine, and attenuated by pretreatment with the potent and selective dopamine uptake blocker GBR 12909; these studies suggest a role for MDMA-released dopamine in the long-term ('neurotoxic') effects of MDMA. The involvement of $/gamma$-aminobutyric acid (GABA) systems in MDMA-induced neurotoxicity remains unclear: whereas inhibition of GABA transaminase prevented the prolonged MDMA-induced deficits, this protective effect was not mimicked by GABA agonists. Blockade of N-methyl- sc D-aspartate receptors with MK-801 or inhibition of cellular calcium overload with flunarizine slightly attenuated the persistent TPH decrease, suggesting a potential minor role for enhanced excitatory amino acid neurotransmission and/or alterations in cellular calcium homeostasis as intermediary processes in MDMA-induced neurotoxicity. Although both dopamine depletion and GABA transaminase inhibition partially blocked the immediate (3-h) MDMA-induced TPH deficit, none of the agents tested completely prevented this initial response. However, the initial decline in enzymatic activity that occurred in vivo following MDMA and other amphetamine analogs could be completely reversed in vitro--provided rats were killed within a short period of time following drug administration--by a 24-h anaerobic exposure to dithiothreitol and reduced iron. This TPH reactivation was associated with an approximate doubling of enzyme Vmax, with no change in enzyme Km for either substrate or cofactor. These studies suggest that MDMA and other amphetamines inactivate central TPH by inducing oxidation of key enzyme sulfhydryl groups, possibly indirectly via the auto-oxidation products of drug-released dopamine.
Type Text
Publisher University of Utah
Subject Pharmacology; Toxiticity
Subject MESH Methamphetamine
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) : role of endogenous dopamine and oxidative damage in the immediate and longterm inactivation of rat central tryptophan hydroxylase." Spencer S. Eccles Health Sciences Library.
Rights Management © Donna Marie Stone.
Format application/pdf
Format Medium application/pdf
Format Extent 2,340,918 bytes
Identifier undthes,4236
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Funding/Fellowship Fellowship from The American Foundation for Pharmaceutical Education; Fellowship from Osco-Skaggs; Fellowship from The University of Utah
Master File Extent 2,340,934 bytes
ARK ark:/87278/s6jq12rs
Setname ir_etd
ID 190679
Reference URL https://collections.lib.utah.edu/ark:/87278/s6jq12rs
Back to Search Results