title: Neurotoxic and pharmacologic studies on enantiomers of the N-methylated analog of cathinone (methcathinone): a new drug of abuse.
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 effects. 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.
authors.affiliation: Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sparago
authors.forename: J
authors.initials: J
authors.lastname: Wlos
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: G
authors.initials: G
authors.lastname: Hatzidimitriou
authors.forename: J
authors.initials: J
authors.lastname: Tolliver
authors.forename: T A
authors.initials: TA
authors.lastname: Dal Cason
authors.forename: J
authors.initials: J
authors.lastname: Katz
authors.forename: G
authors.initials: G
authors.lastname: Ricaurte
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013287:Illicit Drugs / Q000633:toxicity*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017374:Paroxetine / Q000378:metabolism; D011427:Propiophenones / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000697:Central Nervous System Stimulants; D013287:Illicit Drugs; D011427:Propiophenones; D012701:Serotonin; C047806:monomethylpropion; D017374:Paroxetine; D004298:Dopamine