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You have full access to this open access article. MDMA 3,4-methylenedioxymethamphetamine is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA is often ingested with caffeine. 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. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. DNA damage was assayed with the alkaline comet assay. The behavioral changes were measured by the open-field OF test and novel object recognition NOR test. 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. This effect is intensified by inhibition of monoamine oxidase type B MAO-B located in the outer membrane of the mitochondria of serotonergic neurons Leonardi and Azmitia MDMA has been shown to elicit long-lasting neurotoxic effects which vary depending on gender and strain of animals Brodkin et al. Similarly, the damage in serotonergic system was also observed in non-human primates and in the human brain Green et al. Numerous complex mechanisms have been identified as contributors to the neurotoxic effects of MDMA. Oxidative stress and excitotoxicity represent important mechanisms causing neuronal damage by MDMA Cadet et al. MDMA has also been shown to trigger neuroinflammation which seems to be linked with glial activation, in particular microglial activation Costa et al. Other putative mechanisms of MDMA neurotoxicity include hyperthermia, metabolic toxic products, and apoptosis Capela et al. Toxic and inflammatory effects of MDMA are exacerbated by its co-administration with other psychoactive substances Khairnar et al. Caffeine is commonly consumed with MDMA in energy drinks to reduce drowsiness and fatigue, or it is present in illicit drug preparations, e. Molecular mechanism of caffeine action in the brain is based on adenosine receptor antagonism. The targets of caffeine actions include G-protein-coupled adenosine A1 and A2A receptors. It is also suggested that adenosine A1 receptors present on glutamatergic neurons may be involved in striatal DA release Borycz et al. On the other hand, medium-sized spiny neurons projecting to the globus pallidus express D2 receptor Gerfen et al. By contrast, caffeine increases the activity of both types of neurons Johansson et al. Caffeine augmented many effects associated with MDMA use. MDMA-induced hyperthermia and tachycardia but not hyperlocomotion were promoted by caffeine in rats. The results of Khairnar et al. The abovementioned data suggest that caffeine increases MDMA-related neurotoxicity. On the other hand, the results of Ruiz-Medina et al. This raises the question about a long-term caffeine effect on MDMA neurotoxicity. Both drugs were administrated repeatedly in a way mimicking recreational use by young people in dance clubs. In addition, because caffeine could affect behavioral responses, we assessed the effect of chronic caffeine administration on some behavioral parameters associated with MDMA administration. Caffeine and MDMA were dissolved in 0. All injections were done via intraperitoneal ip route, and control animals received their respective vehicles. This cycle of treatments was repeated 3 times as shown on the diagram below. Animals were anesthetized with ketamine 7. After 1 h of the washout period, three basal dialysate samples were collected every 30 min; then, animals were injected with a challenging dose of an appropriate drug as indicated in the figure captions and fraction collection continued for min. At the end of the experiment, the mice were sacrificed and their brains were histologically examined to validate the probe placement. The mobile phase was composed of 0. The flow rate during analysis was set at 0. The chromatographic data were processed by Chromeleon v. Animals were sacrificed by decapitation 3 h after cessation of treatment with drugs. Brains were separated, and several brain regions striatum, frontal cortex were dissected in anatomical borders. Briefly, tissue samples of brain structures were homogenized in ice-cold 0. The mobile phase consisted of 0. The potential of a 3-mm glassy carbon electrode was set at 0. Animals were killed 60 days after termination of drug treatments. The whole cortex was separated in anatomical borders. Next, the brain tissue was minced with surgical scalpel and homogenized in a manual homogenizer with homogenizing solution containing 0. The pellet was resuspended in 0. The nuclei were obtained as a transparent sediment at the bottom. The suspension was mixed with LMA agarose and transferred immediately onto Comet slides. The buffer was drained, and the slides were immersed in alkaline unwinding solution and were left for 45 min in the dark. Next, electrophoresis was run at 21 V for 30 min. The slides were then covered with dye and allowed to dry completely at room temperature in the dark. On the next day, the slides were examined under a fluorescent microscope. DNA damage was presented as an olive tail moment. Olive tail moment is defined as the product of the tail length and the fraction of total DNA in the tail. Tail moment incorporates a measure of both the smallest detectable size of migrating DNA reflected in the comet tail length and the number of damaged pieces represented by the intensity of DNA in the tail. Brains were removed from the skull, and tissue samples including the striatum were collected. The expression of the HPRT1 transcript was quantified at a stable level between the experimental groups to control for variations in cDNA amounts. Cycle threshold values were calculated automatically by iCycler IQ 3. For each mouse, three sections were collected from each of the brain regions analyzed at the following coordinates: from 2. Free-floating sections were rinsed in 0. After completion of incubation with the primary antibody, sections were rinsed three times in 0. After incubation with the secondary antibody, sections were rinsed and immediately mounted onto glass slides coated with gelatin in Mowiol mounting medium. Images of single wavelengths were obtained with an epifluorescence microscope Axio Scope A1, Zeiss, Oberkochen, Germany connected with a digital camera 1. Sections were captured in black and white 8-bit monochrome, and the density of fibers was determined in fixed regions using a threshold level that was kept constant across all images. The pixels were converted into square micrometers by employing a suited calibration, in order to represent the area occupied by a specific immunoreaction product in square micrometers. The final values are expressed as a percentage of the respective vehicle group. No significant differences in the density of immunoreacted fibers were seen between the three coronal sections. For each level of the striatum and mPFC, the obtained value was first normalized with respect to the vehicle, then, values from different levels were averaged. The arena was dimly illuminated with an indirect light of 18 lx. The mice were selected from separate housing cages. Each mouse was diagonally placed in the middle of the box. The behavior of the animals line crossing, center square duration, rearing, stretch attend postures was measured over a 5-min period. The test box was wiped clean between each trial. The laboratory room was dark, and only the center of the open field was illuminated with a W bulb placed 75 cm above the platform. On the first day of the experiment adaptation , mice were placed in the open field for 10 min. On the next day, the animals were placed in the open field for 5 min with two identical objects white tin, 5 cm wide and 14 cm high or green pyramid 5 cm wide and 14 cm high. The time of object interest was measured for each of the two objects separately. Then, 1 h after the first session, the mice were again placed in a free field for 5 min with two different objects, one from the previous session old and the other new white box and green pyramid. The time of object interest was measured for each of the two objects separately sniffing, touching, or climbing. Co-administration of both drugs produced a significantly stronger effect on extracellular DA level than each of the drugs given separately Fig. Time of drug injections is indicated with thick arrows. However, the increase produced by a combination of both drugs was weaker as compared to the effect of MDMA or caffeine given separately Fig. The increase in 5-HT release to ca. The basal extracellular level of 5-HT was decreased from 1. It is clear that the effect of the challenging doses of both psychostimulant drugs on DA release was weaker in groups pretreated chronically with caffeine and MDMA vs. In contrast, the effect of the challenging doses of caffeine and MDMA on 5-HT release was stronger in animals receiving chronic treatment of psychostimulants vs. The increase in DA tissue content was higher in the group treated concomitantly with caffeine and MDMA than in animals receiving these drugs separately Table 2. Caffeine and MDMA given acutely or chronically produced oxidative damage of DNA in nuclei from the mouse cortex as measured 2 months after cessation of treatment Fig. The damage of DNA was stronger after combination of both drugs administered acutely or chronically Fig. The extent of DNA damage was smaller after all treatments when it was measured 24 h after termination of drug administration data not shown. Data represent an olive tail moment. The loss of DNA integrity persisted 60 days after drug administration. Data represent mRNA levels with respect to the control group. Caffeine did not affect those parameters. Bars represent the time of walking and number of crossings a , and time of exploration of novel object b. Our findings indicate that caffeine increased the response of DA neurons to the challenging dose of MDMA while decreasing the response of serotonergic neurons. Furthermore, exploratory and locomotor activities of mice decreased by MDMA were not affected by caffeine, but exploration of novel object in the NOR test was diminished in animals treated with MDMA and caffeine. The pattern of 5-HT release was different showing more stable increase throughout the whole collection time. Moreover, MDMA applied in a single higher dose i. When MDMA was applied chronically 2 days of binge administration per week; this cycle was repeated three times , a weaker response of DA neurons to the challenging dose of MDMA but a stronger response of 5-HT ones was observed. Interestingly, the basal extracellular level of DA in mice receiving MDMA chronically was nearly twofold higher than in control animals, while extracellular 5-HT level was potently decreased. It may be speculated that persistent outflow of DA due to loss of DA uptake capacity may be a cause of increased basal extracellular DA level. Considerable evidence from the literature indicates that internalization of DAT occurs in response to amphetamine treatment Saunders et al. In fact, we observed a decrease in DAT density in the striatum and frontal cortex following chronic exposure to MDMA, which is in line with studies of Saunders et al. This is probably due to compensatory upregulation of 5-HT release machinery resulting from low synaptic 5-HT levels. For instance, Koch and Galloway , Reveron et al. However, some studies report that the activation of 5-HT1A Ichikawa et al. Thus, it may be suggested that long-term exposure to MDMA leads to neuroadaptative changes in sensitivity of serotonin receptors, which may result in differential response of DA and 5-HT neurons, as it is observed in our study. Some data suggest a role of postsynaptic 5-HT2A receptors located on glutamatergic neurons in the neurochemical effects mediated by MDMA. Stimulation of 5-HT2A receptors located on glutamatergic cells in the frontal cortex may elicit an increase in glutamate level leading indirectly to a rise in DA and 5-HT release Alex and Pehek However, it remains unclear how glutamate and GABA release may be involved in upregulation of serotonergic neurons and cause very potent response to the challenging dose of MDMA, as we observed in the present study. However, in contrast to animals pretreated with saline in which caffeine potentiated MDMA-induced increase in 5-HT release, caffeine inhibited the MDMA effect on 5-HT release in animals receiving both psychostimulants repeatedly. It is accepted that the mechanism underlying caffeine influence on neurotransmitter release is related to the blockade of adenosine A1 and A2A receptors. Caffeine may increase DA and glutamate release in the striatum via blockade of inhibitory A1 receptors as was evidenced by a number of studies Borycz et al. The lack of A2A receptors on the striatal monoaminergic neuronal terminals suggests that their role in the control of DA and 5-HT release may be secondary and related to the changes in the activity of striatal output pathways elicited by postsynaptic A2A receptors. These data indicate synergistic interaction between caffeine and MDMA. The difference in results reported by the above-cited studies may be related by way of drug application systemic vs. It may be speculated that persistent blockade of adenosine receptors by caffeine can be responsible for this effect. In the study of Okada et al. However, under A1 receptor blockade by caffeine, the inhibitory effects of A3 receptor were unmasked in addition to the effect of A2 receptor blockade by caffeine Okada et al. Furthermore, it was also demonstrated that 5-HT reuptake activity might be modulated by A3 receptor Okada et al. Thus, the described mechanism of adenosine receptor involvement in the control of 5-HT release and their blockade by caffeine may be responsible for the diminished 5-HT release in response to MDMA and caffeine co-administration. The neurotoxic effect of MDMA in mice seems to be related to dopaminergic and serotonergic systems. The involvement of free radicals in MDMA-induced dopaminergic neurotoxicity in mice was also shown by Peraile et al. Those authors demonstrated that oxidative stress was related with lipid peroxidation and with an increase in superoxide dismutase and decrease in catalase activity. Hydroxyl radical formation together with products of tryptamine oxidation was proposed as the mechanism of MDMA-induced depletion of brain 5-HT by Shankaran et al. Moreover, it was suggested that 5-HT depletion was dependent on 5-HT transporter activity. Barbosa et al. Oxidative damage produced by MDMA may be associated with neuronal cell bodies. Most of the literature has described the striatum as the main target of MDMA neurotoxicity. Here, we provide evidence that other regions are also targets of MDMA neurotoxicity. DNA damage may be a molecular basis for MDMA-induced neuroplasticity with subsequent behavioral and cognitive deficits. At the same time, it slightly but significantly reversed the decrease in striatal DOPAC content and increased DA striatal tissue level. However, it was neuroprotective for DA fibers in the striatum. On the other hand, it potentiated the decrease in cortical SERT fiber density. Thus, caffeine seems to be neuroprotective for striatal dopaminergic fibers, but it seems to increase neurotoxic damage of cortical 5-HT terminals. Moreover, besides damage of cortical 5-HT terminals, caffeine increased MDMA-induced oxidative damage of cortical DNA which suggests degeneration of neuronal cells in this brain region. The neurotoxic effect exerted on cortical neuronal cell bodies may lead to neuroadaptive change of cortical pathways projecting to nigral or raphe nuclei. Thus, overall caffeine effect seems to be partly neuroprotective and partly neurotoxic. This dual action is dependent on doses, the brain region examined, and the schedule of administration as reported by numerous literature. When caffeine was given chronically, it increased activity of antioxidant enzymes superoxide dismutase SOD and catalase CAT in several regions of the rat brain Noschang et al. Aoyama et al. On the other hand, caffeine exhibited prooxidant properties in vitro Azam et al. The neurotoxic potential of caffeine given acutely was evidenced in the mouse brain by enhanced astroglia and microglia reactivities by MDMA Khairnar et al. In contrast, chronic low doses of caffeine exerted anti-inflammatory effects and prevented MDMA-induced neuroinflammatory reaction Ruiz-Medina et al. Study of Frau et al. Thus, caffeine shows differential effects, neuroprotective or neurotoxic, when co-administered with MDMA indicating that the mechanism of action of psychoactive drug combination needs further clarification. This is in line with findings of Benedetto di et al. These data confirm also the role of D1 receptor in MDMA effects, in particular in the development of neurotoxicity after long-term administration Granado et al. The overstimulation of a direct GABAergic pathway with normal functioning of an indirect GABAergic pathway may be responsible for deficit in locomotor activity of mice observed in our study. On the other hand, caffeine co-administered chronically with MDMA decreased the time of exploration of unknown object in the novel object recognition test. It is likely that a combination of both psychostimulants induced deficit in cognitive functions of mice, as also demonstrated by Costa et al. Structural synaptic plasticity of the medial prefrontal cortex was correlated with changes in response to novelty in rats developmentally treated with cocaine Caffino et al. It may be suggested that damage of serotonergic terminals in cortical regions or possible oxidative damage of glutamatergic pathways projecting to the VTA or raphe cell bodies may be responsible for the effect of psychostimulants on cognitive functions. The role of glutamatergic pathway damage by oxidative stress in the hippocampus and cognitive impairment was also shown in mice by Frenzilli et al. Anxiety-like behavior in rats was related to oxidative damage of DNA in the hippocampus by chronic caffeine Noschang et al. The alterations in the brain antioxidant system were suggested to affect the cognitive functions of rats after chronic caffeine ingestion Abreu et al. In conclusion, our data provide evidence that long-term caffeine administration has a powerful influence on dopaminergic and serotonergic neuron functions disturbed by MDMA in the mouse brain and on neurotoxic effects evoked by MDMA. Caffeine potentiates MDMA effect on dopaminergic system and inhibits its effect on serotonergic neurons. Exacerbation of MDMA-evoked oxidative stress may cause damage of serotonergic terminals. Pharmacol Biochem Behav — Pharmacol Ther — Neuroscience — Ann Neurol — J Neurochem — Br J Pharmacol — Neuropsychopharmacology — Article Google Scholar. Ann Med Interne Paris Suppl. Google Scholar. Neurotox Res — Brain Res — NeuroToxicology — J Neurosci — Mov Disord — Psychopharmacology — J Comp Neurol — Trends Pharmacol Sci — Article PubMed Google Scholar. Prog Brain Res — PubMed Google Scholar. Behav Pharmacol — Science — Pharmacol Rep — Pharmacol Rev — Eur J Pharmacol — J Neurol Sci — J Caffeine Res — J Neural Transm — Neuropharmacology — Neurochem Res — J Pharmacol Exp Ther — Neurosci Lett — Eur J Neurosci —9. Academic Press, San Diego. Peacock A, Bruno R, Ferris J, Winstock A Energy drink use frequency among an international sample of people who use drugs: associations with other substance use and well-being. Drug Alcohol Depend — Reveron ME, Maier EY, Duvauchelle CL Behavioral, thermal and neurochemical effects of acute and chronic 3,4-methylenedioxymethamphetamine ecstasy self-administration. Behav Brain Res — JAMA — Biol Psychol — Synapse — Eur J Neurosci — Proc Natl Acad Sci — Shankaran M, Yamamoto BK, Gudelsky GA Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylenedioxymethamphetamine. Prog Neurobiol — Aust J Pharm — Brit Aust J Pharm — Download references. You can also search for this author in PubMed Google Scholar. Reprints and permissions. Neurotox Res 33 , — Download citation. Received : 04 August Revised : 04 October Accepted : 18 October Published : 13 November Issue Date : April Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Neurotoxicity Research Aims and scope Submit manuscript. Download PDF. Abstract MDMA 3,4-methylenedioxymethamphetamine is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. Molecular changes in the nucleus accumbens and prefrontal cortex associated with the locomotor sensitization induced by coca paste seized samples Article 07 February Long-term disruption of tissue levels of glutamate and glutamatergic neurotransmission neuromodulators, taurine and kynurenic acid induced by amphetamine Article 14 March Use our pre-submission checklist Avoid common mistakes on your manuscript. Brain Microdialysis Animals were anesthetized with ketamine 7. Comet Assay Preparation of Nuclear Suspension Animals were killed 60 days after termination of drug treatments. Reaction Protocols Free-floating sections were rinsed in 0. Image Analysis Images of single wavelengths were obtained with an epifluorescence microscope Axio Scope A1, Zeiss, Oberkochen, Germany connected with a digital camera 1. Full size image. Table 3 The density of dopamine transporter DAT and serotonin transporter SERT in the mouse striatum and frontal cortex measured after cessation of treatment with the drugs Full size table. Conclusions In conclusion, our data provide evidence that long-term caffeine administration has a powerful influence on dopaminergic and serotonergic neuron functions disturbed by MDMA in the mouse brain and on neurotoxic effects evoked by MDMA. View author publications. About this article. Copy to clipboard. Search Search by keyword or author Search. 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