Biomedical subjects

J Wlos

Publications and source records attributed to J Wlos.

3 recordsLinked to original sources

PubMed1996

Neurotoxic and pharmacologic 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 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.

Animals↗

PubMed1995

Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy").

The recreational drug (+/)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a methamphetamine derivative that selectively destroys central 5-HT axons and axon terminals in animals and, possibly, humans. The fate of 5-HT neurons following MDMA injury is uncertain. In particular, while it is known that central 5-HT axons can undergo regenerative sprouting after MDMA injury, it has not been determined whether they reestablish the original innervation pattern. To address this question, the present studies examined 5-HT innervation patterns in animals lesioned with MDMA 12-18 months previously. Both rodents (rats) and nonhuman primates (squirrel monkeys) were examined, since there is indication that serotonergic recovery after MDMA injury may be species dependent. 5-HT axon projections were studied neurochemically, autoradiographically and immunocytochemically. In both rodents and nonhuman primates previously lesioned with MDMA, substantial serotonergic axonal sprouting was observed. However, in a few rats and in most squirrel monkeys, the reinnervation pattern was highly abnormal: distant targets (e.g., dorsal neocortex) remained denervated, while some proximal targets (e.g., amygdala, hypothalamus) were reinnervated or hyperinnervated. Although the specific determinants of axonal recovery after MDMA injury remain to be identified, it appears that axons which initially sustain more severe damage, are longer, or are more highly arborized have low probability of recovering. The observation that some brain regions remain denervated, while others are reinnervated or hyperinnervated suggests that, under some circumstances, MDMA injury can lead to a lasting reorganization of ascending 5-HT axon projections. Such lasting changes in brain innervation, documented here in MDMA-treated animals, may have implications for humans using MDMA recreationally.

Afferent Pathways↗

PubMed1993

3,4-Methylenedioxymethamphetamine, serotonin and memory.

The recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is toxic to central serotonin (5-HT) neurons, but few long-term functional consequences of MDMA neurotoxicity have been identified. Because 5-HT has been implicated in learning and memory, the present study was undertaken to examine whether MDMA, by damaging 5-HT neurons, altered mnemonic function on a long-term basis. Rats were treated with saline, MDMA or 5,7-dihydroxytryptamine/desmethylimipramine. The latter treatment group was included to assess the effects of larger 5-HT neuronal lesions than are possible with MDMA. Four weeks after drug treatment, memory was assessed in three different variations of spatial alternation in a T-maze: acquisition with a constant and short delay interval, performance with variable delays and treatment with scopolamine. Upon completion of the behavioral studies, the neurotoxic effects of the drugs were assessed chemically and anatomically. MDMA, which produced a substantial and selective reduction of brain 5-HT, had no effect on choice accuracy. 5,7-dihydroxytryptamine/desmethylimipramine which produced a near-total reduction of 5-HT and a modest reduction of norepinephrine, impaired choice accuracy in all three variations of the task. These data suggest that selective damage to the 5-HT system, like that produced by MDMA, is not sufficient to impair memory, but that combined damage to the 5-HT and norepinephrine systems can disrupt performance in tasks that require recent memory. Because Alzheimer's disease involves impairments in acetylcholine, 5-HT and norepinephrine systems, animals with combined lesions may provide a useful model to study the mnemonic dysfunctions characteristic of this disease.

3,4-Methylenedioxyamphetamine↗