Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

Anna Maria Górska,Krystyna Gołembiowska,Giulia Costa,Ryszard Przewłocki,Micaela Morelli,Katarzyna Kamińska,Agnieszka Wawrzczak-Bargieła,Grzegorz Kreiner

doi:10.1007/s12640-017-9831-9

Anna Maria Górska, Krystyna Gołembiowska + Show 6 more

Open Access

https://doi.org/10.1007/s12640-017-9831-9

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Abstract

MDMA (3,4-methylenedioxymethamphetamine) is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA acts at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) and is known to induce damage of dopamine and serotonin neurons. MDMA is often ingested with caffeine. Caffeine as a non-selective adenosine A1/A2A receptor antagonist affects dopaminergic and serotonergic transmissions. The aim of the present study was to determine the changes in DA and 5-HT release in the mouse striatum induced by MDMA and caffeine after their chronic administration. To find out whether caffeine aggravates MDMA neurotoxicity, the content of DA and 5-HT, density of brain DAT and SERT, and oxidative damage of nuclear DNA were determined. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. The DA and 5-HT release was determined with in vivo microdialysis, and the monoamine contents were measured by HPLC with electrochemical detection. DNA damage was assayed with the alkaline comet assay. DAT and SERT densities were determined by immunohistochemistry, while prodynorphin (PDYN) and proenkephalin were determined by quantitative PCR reactions. The behavioral changes were measured by the open-field (OF) test and novel object recognition (NOR) test. Caffeine potentiated MDMA-induced DA release while inhibiting 5-HT release in the mouse striatum. Caffeine also exacerbated the oxidative damage of nuclear DNA induced by MDMA but diminished DAT decrease in the striatum and worsened a decrease in SERT density produced by MDMA in the frontal cortex. Neither the striatal PDYN expression, increased by MDMA, nor exploratory and locomotor activities of mice, decreased by MDMA, were affected by caffeine. The exploration of novel object in the NOR test was diminished by MDMA and caffeine. Our data provide evidence that long-term caffeine administration has a powerful influence on functions of dopaminergic and serotonergic neurons in the mouse brain and on neurotoxic effects evoked by MDMA.

Highlights

MDMA (3,4-methylenedioxymethamphetamine) known as Becstasy^ is one of the most popular illicit drugs with empathogenic properties
The increase produced by a combination of both drugs was weaker as compared to the effect of MDMA or caffeine given separately (Fig. 1b)
Caffeine potentiated the oxidative damage of nuclear DNA induced by MDMA and had no effect on MDMA-induced decrease in DAT density in the frontal cortex; it reversed MDMA-induced DAT decrease in the striatum

Summary

Introduction

MDMA (3,4-methylenedioxymethamphetamine) known as Becstasy^ is one of the most popular illicit drugs with empathogenic properties. MDMA acting at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) stimulates non-exocytotic release of DA and 5-HT (Baumann et al 2005; Sulzer et al 2005). MDMA has a preferential affinity for SERT over DAT, so it exerts a more pronounced effect on 5-HT release (Rudnick and Wall 1992). After entering the cell via intracellular transport or diffusion, MDMA alters vesicular monoamine transporter (VMAT-2) and causes an increase in cytoplasmic DA and 5-HT concentrations (Sulzer et al 2005). This effect is intensified by inhibition of Neurotox Res (2018) 33:532–548 monoamine oxidase type B (MAO-B) located in the outer membrane of the mitochondria of serotonergic neurons (Leonardi and Azmitia 1994). The damage in serotonergic system was observed in non-human primates and in the human brain (Green et al 2003; Ricuarte et al 1988)

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