N-methylation dissociates methamphetamine's neurotoxic and behavioral pharmacologic effects

Jennifer Fasciano, George Hatzidimitriou, Jie Yuan, Jonathan L. Katz, George A. Ricaurte

Research output: Contribution to journalArticlepeer-review

Abstract

The present studies further examined the effect of N-methylation on the behavioral and neurotoxic effects of methamphetamine. Drug discrimination studies employing a training dose of 1 mg/kg of methamphetamine were used to confirm and extend previous behavioral studies indicating that N-methylation reduced the behavioral activity of methamphetamine 5- to 10-fold. In subsequent neurotoxicity studies, rats received doses of methamphetamine (10 mg/kg, s.c., every 6 h x 5) or its N-methylated derivative, N,N-dimethyl- amphetamine (100 mg/kg, s.c., every 6 h x 5) that, based on the results of the behavioral studies, would be expected to produce behaviorally equivalent effects. Saline-treated rats served as controls. Two weeks after treatment, the status of brain dopamine (DA) and serotonin (5-HT) neurons was assessed by measuring DA and 5-HT axon terminal markers. As anticipated, methamphetamine produced neurochemical deficits indicative of DA and 5-HT axon terminal damage. By contrast, despite the fact that it was given at a dose behaviorally equivalent to methamphetamine, N-N-dimethylamphetamine failed to produce signs of DA or 5-HT neurotoxicity. These results indicate that N-methylation dissociates methamphetamine's neurotoxic and behavioral pharmacologic effects, and suggest that it may be possible to separate the neurotoxic and pharmacologic effects of other substituted amphetamine derivatives with potentially useful clinical activity (e.g. fenfluramine and methylenedioxymethamphetamine).

Original languageEnglish (US)
Pages (from-to)115-120
Number of pages6
JournalBrain research
Volume771
Issue number1
DOIs
StatePublished - Oct 10 1997

Keywords

  • Amphetamine
  • Dopamine
  • Neurotoxicity
  • Serotonin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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