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Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog.

M Johnson1, G R Hanson, J W Gibb

  • 1Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.

European Journal of Pharmacology
|June 20, 1989
PubMed
Summary

This study investigated how N-methyl-D-aspartate (NMDA) receptors affect tryptophan hydroxylase (TPH) activity after methamphetamine or MDMA exposure. NMDA receptor blockade partially protected against methamphetamine

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Repeated high doses of methamphetamine (MAP) and 3,4-methylenedioxymethamphetamine (MDMA) are known to decrease neostriatal tryptophan hydroxylase (TPH) activity.
  • Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis, and its activity is crucial for regulating central serotonergic neurotransmission.

Purpose of the Study:

  • To evaluate the role of N-methyl-D-aspartate (NMDA) receptors in the reduction of neostriatal TPH activity induced by repeated high doses of methamphetamine or MDMA.
  • To investigate potential differences in the mechanisms underlying the TPH activity decrease caused by methamphetamine and MDMA.

Main Methods:

  • Rats were administered four injections of methamphetamine (15 mg/kg) or MDMA (10 mg/kg) at 6-hour intervals.

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  • Some rats received coadministration of MK-801 (2.5 mg/kg), an NMDA receptor antagonist.
  • Neostriatal TPH activity was measured 18-20 hours after the final drug administration.

    • Main Results:

    • Both methamphetamine and MDMA treatments significantly reduced neostriatal TPH activity to 26% and 34% of control levels, respectively.
    • Coadministration of MK-801 significantly attenuated the methamphetamine-induced decrease in TPH activity, restoring it to 66% of control.
    • MK-801 did not alter the MDMA-induced decrease in TPH activity.

    Conclusions:

    • Excitatory amino acids, acting through NMDA receptors, appear to play a role in the methamphetamine-induced decline of central TPH activity.
    • The findings suggest that the mechanisms by which methamphetamine and MDMA reduce TPH activity may differ, with NMDA receptor involvement being specific to methamphetamine's effects.