Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated.

Dopamine is not essential for the development of methamphetamine-induced neurotoxicity.

It is widely believed that dopamine (DA) mediates methamphetamine (METH)-induced toxicity to brain dopaminergic neurons, because drugs that interfere with DA neurotransmission decrease toxicity, whereas drugs that increase DA neurotransmission enhance toxicity. However, temperature effects of drugs that have been used to manipulate brain DA neurotransmission confound interpretation of the data. Here we show that the recently reported ability of L-dihydroxyphenylalanine to reverse the protective effect of alpha-methyl-para-tyrosine on METH-induced DA neurotoxicity is also confounded by drug effects on body temperature.

Heating induces aggregation and decreases detection of serotonin transporter protein on western blots.

In recent years, there has been growing interest in the use of Western blot analysis to monitor changes in the abundance of the serotonin transporter (SERT) protein. In the Western blot procedure, heat denaturation is a common, early step. We now report that heating samples to 90 degrees C decreases the abundance of the SERT protein band and causes dispersion of a majority of the SERT signal to a high molecular weight smear.

Loss of serotonin transporter protein after MDMA and other ring-substituted amphetamines.

We studied in vivo expression of the serotonin transporter (SERT) protein after 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine (PCA), or fenfluramine (FEN) treatments, and compared the effects of substituted amphetamines to those of 5,7-dihydroxytryptamine (5,7-DHT), an established serotonin (5-HT) neurotoxin. All drug treatments produced lasting reductions in 5-HT, 5-HIAA, and [(3)H]paroxetine binding, but no significant change in the density of a 70 kDa band initially thought to correspond to the SERT protein. Additional Western blot studies, however, showed that the 70 kDa band did not correspond to the SERT protein, and that a diffuse band at 63-68 kDa, one that had the anticipated regional brain distribution of SERT protein (midbrain>striatum>neocortex>cerebellum), was reduced after 5,7-DHT and was absent in SERT-null animals, was decreased after MDMA, PCA, or FEN treatments.

Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys.

To examine the relationship between temperature (ambient and core), dopaminergic neurotoxicity, and plasma drug [methamphetamine (METH)] and metabolite [amphetamine (AMPH)] concentrations, two separate groups of squirrel monkeys (n = 4-5 per group) were treated with METH (1.25 mg/kg, given twice, 4 h apart) or vehicle (same schedule) at two different ambient temperatures (26 and 33 degrees C). Core temperatures and plasma drug concentrations were measured during the period of drug exposure; striatal monoaminergic neuronal markers in the same monkeys were determined 1 week later.