NEUROTOXIC AND PHARMACOLOGICAL STUDIES ON ENANTIOMERS OF THE N-METHYLATED ANALOG OF CATHINONE (METHCATHINONE) - A NEW DRUG OF ABUSE

These studies evaluated neurotoxic and pharmacologic properties of the R(+) and S(-) enantiomers of methcathinone, a psychostimulant drug th at 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 m eans of silver degeneration studies; pharmacologic effects were evalua ted by measuring locomotor stimulation. Methcathinone produced dose-re lated neurotoxic and locomotor stimulant effects which were species- a nd enantiomer-dependent, In mice, although both enantiomers produced t oxic effects on DA neurons, the R(+) enantiomer was more potent, and n either enantiomer produced long-term effects on 5-HT neurons, By contr ast, in behavioral studies, both enantiomers increased mouse locomotor activity, but the S(-) enantiomer was more potent, which suggests tha t methcathinone's neurotoxic and locomotor stimulant effects may be se parable. Additional studies were done with rats, because mice are ofte n refractory to 5-HT neurotoxicity induced by amphetamines. In the rat , both enantiomers produced toxic effects on DA neurons, only S(-)-met hcathinone produced toxic effects on 5-HT neurons, and both enantiomer s produced comparable locomotor stimulant effects. Together, these res ults indicate that: 1) Methcathinone has the potential to damage DA an d 5-HT neurons; 2) Methcathinone neurotoxicity is enantiomer and speci es dependent; 3) Methcathinone's neurotoxic and locomotor stimulant ef fects are dissociable in mice but not rats; and 4) N-methylation confe rs 5-HT toxic activity onto cathinone, the N-desmethyl derivative of m ethcathinone, which is known to lack 5-HT neurotoxic activity.