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Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters

A E Fleckenstein1, M L Beyeler, J C Jackson

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

European Journal of Pharmacology
|April 18, 1997
PubMed
Summary
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This study challenges the hypothesis that dopamine uptake into serotonin neurons causes methamphetamine neurotoxicity. Findings suggest serotonin transporters may not mediate dopamine uptake, indicating alternative mechanisms for drug-induced neuronal damage.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Neurotoxicology

Background:

  • Methamphetamine neurotoxicity is hypothesized to involve dopamine uptake into serotonin neurons.
  • This hypothesis is supported by the requirement of dopamine and the inhibitory effect of serotonin transporter inhibitors on methamphetamine-induced deficits.

Purpose of the Study:

  • To investigate the role of serotonin transporters in methamphetamine-induced neurotoxicity.
  • To examine whether serotonin transporters mediate dopamine uptake into serotonergic terminals.

Main Methods:

  • Assessing [3H]dopamine uptake into rat brain synaptosomes after p-chloroamphetamine-induced neurotoxicity.
  • Comparing the inhibitory concentrations (IC50) of citalopram and fluoxetine for [3H]dopamine transport.
  • Investigating the effect of fluoxetine pretreatment on methamphetamine-induced decreases in tryptophan hydroxylase activity.

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Main Results:

  • p-chloroamphetamine-induced serotonergic neurotoxicity did not decrease [3H]dopamine uptake into synaptosomes.
  • Citalopram showed a higher IC50 for [3H]dopamine transport than fluoxetine, despite higher affinity for the serotonin transporter.
  • Fluoxetine pretreatment prevented methamphetamine-induced decreases in tryptophan hydroxylase activity, independent of body temperature or drug concentration.

Conclusions:

  • Serotonin transporters may not mediate dopamine uptake, challenging the proposed mechanism for methamphetamine neurotoxicity.
  • Alternative mechanisms likely explain how serotonin transporter inhibitors attenuate methamphetamine-induced serotonergic deficits.
  • Drug-induced changes in body temperature or methamphetamine concentration are insufficient to cause serotonergic neuronal dysfunction.