Neurotoxic and pharmacologic studies on enantiomers of the N-methylated analog of cathinone (methcathinone): A new drug of abuse

Merrill Sparago, Jennifer Wlos, Jie Yuan, George Hatzidimitriou, James Tolliver, Terry A. Dal Cason, Jonathan Katz, George Ricaurte

Research output: Contribution to journalArticlepeer-review

Abstract

These studies evaluated neurotoxic and pharmacologic properties of the R(+) and s(-) enantiomers of methcathinone, a psychostimulant drug that has surfaced in the illicit drug market, primarily in the S(-) form. Neurotoxic potential toward brain dopamine (DA) and serotonin (5-HT) neurons was assessed by measuring DA and 5-HT axonal markers and by means of silver degeneration studies; pharmacologic effects were evaluated by measuring locomotor stimulation. Methcathinone produced dose-related neurotoxic and locomotor stimulant effects which were species- and enantiomer-dependent. In mice, although both enantiomers produced toxic effects on DA neurons, the R(+) enantiomer was more potent, and neither enantiomer produced long-term effects on 5-HT neurons. By contrast, in behavioral studies, both enantiomers increased mouse locomotor activity, but the S(-) enantiomer was more potent, which suggests that methcathinone's neurotoxic and locomotor stimulant effects may be separable. Additional studies were done with rats, because mice are often refractory to 5-HT neurotoxicity induced by amphetamines. In the rat, both enantiomers produced toxic effects on DA neurons, only S(-)- methcathinone produced toxic effects on 5-HT neurons, and both enantiomers produced comparable locomotor stimulant affects. Together, these results indicate that: 1) Methcathinone has the potential to damage DA and 5-HT neurons; 2) Methcathinone neurotoxicity is enantiomer and species dependent; 3) Methcathinone's neurotoxic and locomotor stimulant effects are dissociable in mice but not rats; and 4) N-methylation confers 5-HT toxic activity onto cathinone, the N-desmethyl derivative of methcathinone, which is known to lack 5-HT neurotoxic activity.

Original languageEnglish (US)
Pages (from-to)1043-1052
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume279
Issue number2
StatePublished - Nov 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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