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In Vitro Reactivation of Rat Cortical Tryptophan Hydroxylase Following In Vivo Inactivation by Methylenedioxymethamphetamine

Donna M. Stone, Glen R. Hanson, James W. Gibb

Journal of Neurochemistry August 1, 1989 DOI: 10.1111/j.1471-4159.1989.tb07372.x (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Animal experimental study Peer reviewed
Population Rat brain cortical tissue
Interventions 3 methamphetamine dithiothreitol Fe2+ cycloheximide
Topics MDMA
Key findings MDMA acutely and reversibly inactivates rat brain tryptophan hydroxylase, with recovery within 24 hours at low doses that does not require new enzyme synthesis; reactivation in vitro by reducing agents suggests oxidation of key sulfhydryl groups. Enzyme inactivated beyond three days after treatment could not be reactivated, which the authors propose as an index of developing MDMA-induced neurotoxicity.

Abstract

Abstract: The activity of tryptophan hydroxylase (EC 1.14.16.4) from rat brain was significantly decreased 1 h following a single systemic injection of 3,4‐methylenedioxy‐methamphetamine (MDMA) when assessed ex vivo by ra‐dioenzymatic assay or in vivo by the quantitation of 5‐hy‐droxytryptophan accumulation following central L‐aromatic amino acid decarboxylase inhibition. Recovery of enzymatic activity in vivo, which occurred within 24 h of low‐dose MDMA treatment, appeared not to involve synthesis of new enzyme protein, because the return of enzymatic activity was not prevented by prior cycloheximide. Acutely MDMA‐depressed cortical tryptophan hydroxylase activity could be completely restored in vitro by a prolonged (20‐24 h) anaerobic incubation in the presence of dithiothreitol and Fe2+at 25°C; partial reconstitution occurred when 2‐mercapto‐ethanol was substituted for dithiothreitol. Cortical tryptophan hydroxylase acutely inactivated by methamphetamine or p‐chloroamphetamine could be similarly reactivated. MDMA‐inactivated cortical tryptophan hydroxylase derived from rats killed later than 3 days after drug treatment could not be significantly reactivated under the conditions described above, indicating the development of irreversible enzymatic damage. Kinetic analysis of enzyme reactivation revealed an approximate doubling of enzyme Vmax with no change in enzyme affinity for either substrate, tryptophan, or pterin cofactor. These studies suggest that MDMA and its congeners inactivate central tryptophan hydroxylase by inducing oxidation of key enzyme sulfhydryl groups. The reactivation capacity of drug‐inactivated enzyme at various times after MDMA treatment may provide a means of assessing the development of MDMA‐induced neurotoxicity.

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.

Study Year Design Participants
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study
Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Rats 1998 Experimental study
Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Squirrel monkeys treated with MDMA 1999 Observational cohort

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