Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions

Abstract

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.

Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain

“…Concentrations of 5-HT and 5-HIAA in the striatum, frontal cortex, and hippocampus were determined by HPLC with electrochemical detection as previously described (Goñi-Allo et al, 2006). These brain areas were chosen because the neurotoxic effects of MDMA are limited to the 5-HT terminals of the serotonergic neurotransmitter system, insofar as cell bodies in the raphe nuclei are not damaged by MDMA (O'Hearn et al, 1988;Kovács et al, 2007).…”

The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity

“…Concentrations of 5-HT and 5-HIAA in the brain regions of the rats were determined by HPLC-ED as previously described (Goni-Allo et al 2006). …”

“…Despite the efforts made during the last two decades, the mechanisms underlying MDMA toxicity remain unclear. Oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to play a major role in the neurotoxicity produced by different amphetamine derivatives (Goni-Allo et al 2006;Quinton and Yamamoto 2006). The focus of this investigation was on the involvement of hyperthermia and MDMA metabolic disposition in the aforementioned mechanisms of neurotoxicity.…”

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease

“…Striatal concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by high performance liquid chromatography (HPLC) with electrochemical detection, as described previously (Goni-Allo et al, 2006).…”