This review (2022) explores the cellular mechanisms involved in MDMA neuroinflammatory effects. The protective effects of adenosine receptors is also discussed.
3,4-methylenedioxymethamphetamine (MDMA) is a worldwide abused psychostimulant, which has neurotoxic effects on dopaminergic and serotonergic neurons in both rodents and non-human primates. Adenosine acts as a neurotransmitter in the brain through the activation of four specific G-protein-coupled receptors and it acts as a neuromodulator of dopamine neurotransmission. Recent studies suggest that stimulation of adenosine receptors oppose many behavioural effects of methamphetamines. This review summarizes the specific cellular mechanisms involved in MDMA neuroinflammatory effects, along with the protective effects of adenosine receptors.
Kermanian and colleagues introduce MDMA (3,4-methylenedioxymethamphetamine, commonly known as ecstasy) as a widely used recreational psychostimulant with acute psychoactive effects such as euphoria, heightened sociability and sensory sensitivity, but also with significant acute adverse effects including hyperthermia, cardiovascular strain and cognitive disturbances. Earlier research has implicated MDMA in neurotoxic effects on serotonergic and, to a lesser extent, dopaminergic systems in animals and non-human primates, with particular vulnerability reported in limbic and cortical regions such as the hippocampus, amygdala and prefrontal cortex. The authors note that these neurochemical alterations are thought to contribute to memory and learning deficits observed in some human users, although human evidence for persistent serotonergic neurotoxicity remains inconclusive. This review sets out to summarise mechanisms linking MDMA exposure to neuroinflammation and neuronal injury, and to examine the modulatory and potentially protective roles of adenosine receptors (A1, A2A, A2B and A3) in those processes. Kermanian frames the paper around two linked questions: which brain regions and neurotransmitter systems are affected by MDMA, and how might adenosinergic signalling influence MDMA-induced neuroinflammation and addiction-related processes. The authors emphasise the translational interest of adenosine receptors as targets that modulate dopamine, serotonin and glial responses, while flagging unresolved and contradictory findings in the literature.
Papers cited by this study that are also in Blossom
Jerome, L., Feduccia, A. A., Wang, J. B. et al. · Psychopharmacology (2020)
Müller, F., Brändle, R., Liechti, M. E. et al. · Neuroscience and Biobehavioral Reviews (2019)
Nichols, D. E. · Journal of Psychoactive Drugs (1986)
Vegting, Y., Reneman, L., Booij, J. · Psychopharmacology (2016)
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Kermanian and colleagues compile evidence from epidemiological reports, animal experiments and imaging studies to describe MDMA's neural and inflammatory effects. Epidemiologically, several prevalence estimates are cited: the United Nations estimate of approximately 12 million lifetime users worldwide, more than 17 million persons in the United States reporting lifetime use by 2014, and European lifetime-use estimates around 4.2% in 2017 with country variation (0.3%–6.6%). At the neurochemical level, the review emphasises that MDMA acts as a substrate for monoamine transporters, leading to release of serotonin (5-HT), dopamine (DA) and norepinephrine and thereby perturbing serotonergic, dopaminergic, adenosinergic and glutamatergic systems. Preclinical findings summarised include reports of substantial acute increases in monoamines (one cited study observed cerebral DA increase of 86% and serotonin increase of 123% in mice after MDMA), and longer-term reductions in markers of serotonergic function (lower 5-HT release, reduced SERT binding and decreased tryptophan hydroxylase activity) in neocortex, hippocampus and striatum. The authors report that cognitive impairments in recreational users most consistently involve encoding deficits for new material, with some persistence after abstinence, though they acknowledge that definitive demonstration of persistent serotonergic neurotoxicity in humans remains lacking. Dopaminergic effects are described as secondary but important: repeated or juvenile MDMA exposure in animals has been associated with reductions in dopamine cell bodies/terminals, decreased dopamine content in striatum and substantia nigra, and behavioural deficits in learning and motor function. Mechanistic contributors cited include dopamine-mediated oxidative stress, mitochondrial dysfunction, hyperthermia-enhanced toxicity and receptor-mediated processes; for example, D1 and D2 receptor activity is implicated in MDMA-induced dopaminergic damage and in modulation of hyperthermia and astrogliosis. On neuroinflammation, the review documents that MDMA and related amphetamine derivatives induce rapid microglial and astroglial activation in striatum, cortex and hippocampus, with increased markers such as GFAP and microglial reactive indicators, and elevated pro-inflammatory mediators including inducible nitric oxide synthase and interleukins. Experimental inhibition of microglial activation (for example with minocycline) is noted to protect against amphetamine-induced neurotoxicity in animal models, supporting a mechanistic role for glial-driven inflammation in neuronal injury. A substantial portion of the results synthesis centres on adenosine receptor biology. The authors describe the four subtypes: A1R (widely expressed in cortex, hippocampus and glia, generally inhibitory and neuroprotective), A2AR (abundant in striatum and implicated in modulating synaptic plasticity, glutamate release and glial reactivity), A2BR (lower expression, present on astrocytes, neurons and microglia, with less well characterised roles) and A3R (low density, dose- and time-dependent effects, both neuroprotective and neurotraumatic reported). Reported functional interactions include A1R co-localisation with D1 receptors and A2AR co-localisation with D2 receptors, with A2AR activation decreasing D2 receptor affinity and thereby modulating dopaminergic signalling. Adenosine receptors also influence serotonin release: A1R stimulation decreases extracellular 5-HT while A2AR stimulation increases it. Experimental data cited indicate that adenosine receptor antagonists can enhance MDMA-induced DA and 5-HT release in mouse striatum, and that modulation of A2AR signalling affects glial secretion of proinflammatory mediators. The authors report mixed and sometimes contradictory findings regarding adenosine receptor roles in inflammation: A2AR activation has been robustly associated with anti-inflammatory effects in many models, yet timing, concentration and cell-type context can produce pro- or anti-inflammatory outcomes. A2AR agonists reduced TNF-α and neutrophil infiltration in stroke and spinal cord trauma models, while A2AR blockade has been reported to control microglial activation in some neurodegeneration and trauma models. A3R and A2BR roles are described as controversial or less well defined. Finally, experimental manipulations of adenosine signalling alter drug-related behaviours in animals: A2AR antagonists modulate reinstatement in heroin self-administration models, A1R agonists in nucleus accumbens inhibit cocaine seeking, and A3R deletion increased sensitivity to methamphetamine toxicity in mice.
Kermanian and colleagues interpret the assembled literature to suggest that neuroinflammation is a plausible contributing mechanism for MDMA-related neurotoxicity, with activated microglia and astrocytes releasing cytokines, reactive oxygen and nitrogen species that can damage vulnerable monoaminergic terminals. They argue that adenosine receptors represent a biologically plausible modulatory system because of their capacity to regulate neurotransmitter release, glial reactivity and metabolic processes; in particular, A1R and A2AR are highlighted as important determinants of neuronal resilience versus inflammatory responses. The authors position these conclusions within the prior literature by noting both convergent animal data (microglial activation, GFAP upregulation, protection with microglial inhibitors) and inconsistent or incomplete human evidence for persistent monoaminergic damage. They note examples where adenosine receptor ligands produce protective effects in preclinical models (for example A2AR agonists reducing TNF-α in stroke models) but also highlight studies showing opposing outcomes depending on dose, timing, receptor subtype and experimental context. Key limitations acknowledged include the paucity of focused studies specifically addressing adenosine receptors in MDMA-induced neuroinflammation, heterogeneity across experimental paradigms (species, dosing regimens, developmental timing), and the difficulty of extrapolating animal findings to human users. The authors also point out pharmacological challenges for therapeutic targeting of adenosine receptors, including their wide physiological distribution, potential for tolerance with repeated ligand exposure, and difficulty achieving tissue- or cell-type selectivity. In terms of implications, the review proposes that adenosine receptor modulation could be a promising avenue for mitigating MDMA-related neuroinflammation and possibly for influencing addiction-related behaviours, but stresses the need for more mechanistic studies to resolve contradictory findings and to characterise receptor-specific effects in the context of acute versus chronic MDMA exposure. The authors recommend further research into molecular mechanisms, dosing paradigms and translational models before considering clinical applications.
The authors conclude that adenosine receptors may contribute to neuroprotection against MDMA-induced damage primarily by inhibiting pathological glial activation, yet current evidence is limited and sometimes contradictory. Given the broad and diffuse actions of the adenosinergic system, therapeutic targeting in the context of drug abuse carries risks as well as potential benefits; the review phrases this as a "double-edged sword." Kermanian and colleagues call for additional studies to clarify receptor-specific mechanisms and to determine whether modulation of adenosine signalling can be safely and effectively harnessed to prevent or reverse MDMA-related neuroinflammation.
The popular recreational drug, "ecstasy" (3,4 methylenedioxymethamphetamine; MDMA), is a phenethylamine structurally similar to both amphetamine and mescaline, a hallucinogenic and intoxicating compound present in mescal buttons from the peyote cactus. This laboratory-made drug is available in forms of pill, tablet, capsule and injection which may be mixed with other substances such as ephedrine, amphetamine, and methamphetamine). Although, MDMA has been empirically classified into a newfound pharmacological class nominated "entactogens" , because of a specific psychoactive profile, it is identified as classic hallucinogens and stimulants. It is increasingly becoming a worldwide trend especially among adolescents and young adults. MDMA has some false positive acute psychological effects which include feelings of euphoria, elevated self-confidence and boosted sensory watchfulness(Figurasin and Maguire 2019). Intake of MDMA has been related to acute adverse reactions such as hyperthermia, hypertension, tachycardia, acute myocardial infarction and increased motor activities trismus (jaw-clenching)). In addition some abnormality associated with character such as moderate de-realization and de-personalization, J o u r n a l P r e -p r o o f cognitive disturbances, elevated anxiety, and loss of appetite. The transition from drug to drug abuse involves a number of drug-induced neural adaptations that lead to uncontrolled drug use and the inability to avoid it following repeated exposure .It has been proven that increasing DA neurotransmission is the first critical step in this process.Activation of the mesocorticolimbic DA system via cells in the abdominal tegmental region that attach to the abdominal striatum (accumbens nucleus involved in reward assignment), the prefrontal cortex (involved in prominent assignment and executive function), and the amygdala (involved in emotional responses) and the hippocampus (involved in long-term strengthening and memory), reinforces repeated use of the drug, which leads to addiction. Glutamatergic reciprocal efferents travel from these sites to the abdominal tegmental region and the nucleus accumbens to moderate the effects of these drugs. Following acute exposure to an enhancer such as MDMD, DA diffusion increases in these distal regions of the ventral dopamine system, and these initial effects trigger a cascade of additional brain responses that aid in the transition from drug to drug abuse. J o u r n a l P r e -p r o o f MDMA acts as a substrate for various types of vesicular carrier monoamine transporter proteins and thus releases serotonin (5HT), dopamine (DA) and norepinephrineand because of interaction with the function of dopaminergic, serotonergic, adenosine and glutaminergic systems, MDMA influences various structures of the brain such as cortex, hippocampus and limbic system, which play important roles in learning, memory, long-term information storage and spatial reasoning. We offer a review of the results of studies on the MDMA-related neurotoxicity and role of adenosine receptors on neuro-inflammation and addiction. In addition to the emphasis on the adenosine system, various regions of the brain affected by ecstasy use, as well as the serotonin / dopamine system, are discussed.
In 1912, a German pharmaceutical company, developed MDMA as a compound to synthesize medications that control bleeding, not to control appetite as is often incorrectly cited. For several years MDMA was one of many legal recreational agents taken by young generation who seeks spiritual enlightenment, and it was widely available on the street. J o u r n a l P r e -p r o o f Even though MDMA defined as a substances with no currently accepted medical use and a high potential for abuse, the use of that in many societies seems to be expanding. The United Nations has estimated that the consumption of ecstasy around the world has affected 12 million peoples). In the United States, ecstasy use reportedly increased significantly during the 1990s and early 2000s.The National Survey on Drug Use and Health have declared that in 2014 more than 17 million persons aged 12 or older reported using MDMA at least once in their lifetimes. Ecstasy use has also increased in Australia. Data from the National Drug Strategy Household Survey indicated that nearly one million people had used ecstasy at some time during their lives and levels of use in the past year reached around 3% of the adult population in 2001). The European Union Drug Administration has revealed, in its annual report, that between 0.5 to 3% of the European adult society are addicted to ecstasy consumption, and the highest intake is among young people aged 15 to 16. In 2017, European Drug Report estimated that 4.2 % of European adults between 15-to 64-year-old, have used MDMA/ecstasy at some time in their lives with an estimates ranging from 0.3 % in Cyprus, Lithuania and Romania to 6.6 % in the J o u r n a l P r e -p r o o f Netherlands.In Southeast Asia, ecstasy use is typically restricted to youth from higher socio-economic class where the drug is taken in at entertainment venues. However, there have been reports of ecstasy use among other population groups).In the 1990s, Southeast Asia experienced a boom in the production and consumption of amphetamine-type stimulants (ATS), in particular methamphetamines (METH) specifically in higher use countries including the Philippines, Thailand and Lao PDR. In West Asia, the use of ATS tablets sold as Captagon appears to be more common, whereas in East and Southeast Asia, methamphetamine is the primary ATS used. In 2011, the annual prevalence of ecstasy use in Asia is estimated to be 0.1-0.6 % of the population aged 15-64 years with an increasing use in China and Taiwan. Over the past few years, the use of amphetamines has increased dramatically in, neuroinflammation, and memory and cognitive impairment. Therefore this question arises about which parts of brain are influenced by addiction to consumption of ecstasy? Evidence from previous research suggests that the hippocampus, amygdala, and frontal cortex are strongly affected by ecstasy. The results of brain imaging studies have confirmed that the metabolic rate of glucose in the hippocampus, the amygdala complex, the neocortex, putamen /caudate and thalamic nucleus are bilaterally reduced, which in turn leads to particularly vulnerable to MDMA neurotoxicity, specifically hyperthermia, monoamine oxidase metabolism of dopamine and serotonin, mitochondrial dysfunction, dopamine oxidation, serotonin transporter action, formation of peroxinitrite, glutamate excitotoxicity, and importantly deficits in serotonergic biochemical markers. How metabolic glucose rate and neurotoxicity may be linked refer to persistent episodes of hyperglycemia. The uptake of glucose J o u r n a l P r e -p r o o f into nerve tissue depends on its extracellular concentration, which passes through the glucose transporter attached to the cell membranes of the blood-brain barrier. Mentioned processes cause toxicity to neurons following impaired glucose metabolism. Because the hippocampus is part of the limbic system which contains serotonergic receptors, it is responsible for memory processing, emotion control, judgment, love and motivation. Also, there are some documents that not only MDMA disrupts function of mentioned areas but also the occipital area is particularly impressed by ecstasy). What lesion is happened due to occipital lobe injury is in line with work but because of close functional relationship between visual cortex and hippocampus, visual memory can be affected by extensive exposure to ecstasy. The hippocampus is the main area in cognitive activities, especially memory). Its special anatomical structure in organizing neurovascular circuits has made it particularly assailable to homeostatic alteration. Animal and human studies have proven that the hippocampus and prefrontal cortex are the most vulnerable regions of the brain that are affected by toxic effects of MDMAand due to key role of hippocampal complex in memory and cognitive capability, use of amphetamine derivate can injure these abilitiesJ o u r n a l P r e -p r o o f. The exact mechanisms that are participate in cognitive pathways have not been clear but foregone researchers believe that extraordinary depletion of serotonin in hippocampus and prefrontal cortex hyperstimulate 5-HT receptors and causes deficiency in normal function of these regions which related to memory and personality.
Neurotoxic effect of MDMA (`ecstasy') on 5-HT neurons Serotonin, known as the hormone of happiness, has regulatory roles in many important physiological functions such as food intake, reproduction, immunity, nervous function, and anti-stress responses. It has been said, increasing the secretion of this neurotransmitter causes overflow of it transmutes to the outer space of the synaptic gap, and has a different mentioned effect by the binding to the serotonin extra-synaptic receptors. Serotonergic neurons are mainly located in raphe nuclei, but their axons are distributed in different regions. The hippocampus is the main target of serotonergic afferents which is part of limbic system limbic system. As in previous studies had confirmed, the limbic system is associated with memory processing, judgment, impact and motivation or organizing planned actions. Distribution of serotonergic neural pathways and J o u r n a l P r e -p r o o f expressing multiple serotonin receptors in the hippocampus is associated with memory and mood in animal. CNS serotonin has at least three important roles: (1) classical neurotransmitter actions in cell-cell signaling, (2) vasoconstrictive effects via innervation of intracranial blood vessels, and (3) cytoskeletal effects, including positive coupling to the activity of growth factors (brain derived nerve growth factor (BDNF) and S100B implicated in maintaining neuronal integrity) .Thus, MDMA abuse could potentially result in absolute or relative reductions in CNS gray matter via transmitter-mediated toxicity, vascular ischemia or hemorrhage, or loss of neurotrophic effects. Drug and non-drug agents can induce mild, moderate to severe symptoms, known as serotonergic syndrome. Mild and moderate type can be transformed into severe form that is life-threatening. This syndrome is due to the excessive discharge of serotonin in the brain tissue. The other neurotransmitter such as dopamine, noradrenaline, GABA or glutamates, probably secondary to serotonergic syndrome changed). There are 14 type of 5-HT receptors, and receptors 5-HT1A and 5-HT2A have been identified as the main actors in the creation of serotonergic syndrome. Drug factors increase serotonin extracellular levels while non-drug factors cause J o u r n a l P r e -p r o o f changes in the irritability of serotonin extra-synaptic receptors. Many drugs, including MDMA, can easily increase 5-HT that activates both synaptic and extrasynaptic 5-HT1A receptors). However, 5-HT2A receptors activates with a concentration of 1000 times more than what is needed to 5-HT1A receptors activation. Usual symptoms include hyperthermia, hypertension, confusion, agitation, and seizures. Sometimes individuals who suffer from this syndrome also have nausea, sweating, and headache symptoms). These receptors are widespreading distributed in areas of the brain like hypothalamus and prefrontal cortex. The extra-synaptic serotonin receptors in the hypothalamus, by stimulating hypothalamic-pituitary-adrenal pathway, result in hypothermia). In the mammalian brain, the serotonergic neuronal fibers, which are the main target of ecstasy, originate from the raphe nucleus of the brain stem. The dorsal and medial raphe nuclei innervate upper structure of brain, including the frontal cortex and the hippocampus. The frontal cortex plays a key role in risk taking, executing functions, and memory which its malfunction result in neuropsychiatric diseases. Meanwhile hippocampus has a fundamental role to forming basic and spatial memory. Therefore, drugs that contain amphetamine compounds, such as ecstasy, can lead to socioaffective behaviors, symptoms of mood dysregulation, due to inordinate J o u r n a l P r e -p r o o f activity of 5-HT receptors. One research showed that heroin and ecstasy at high doses significantly activate serotonergic neurons by inhibiting GABA neurons in rats. Due to neurotoxicity in high doses, MDMA has been shown to reduce longterm 5-HT secretion, decrease 5-HT reuptake and the number of SERT binding sites, and reduce tryptophan hydroxylase activity in the neocortex, hippocampus, and striatum in laboratory animals. Chronic Memory is a process through which learned information is stored, and newly formed memories are susceptible to disruption and must be stabilized for long-term storage through a process referred to as memory consolidation. Relative to drug-naive controls and ecstasy/MDMA -naive polydrug controls, the most consistent neurocognitive impairment observed in recreational J o u r n a l P r e -p r o o f ecstasy/MDMA users demonstrate memory and learning deficits). These memory deficits can also persist after prolonged abstinence from ecstasy/MDMA. Despite the dysfunction caused by the serotonergic system, it should be noted that, neither memory impairments that result from ecstasy use are due to involvement of the serotonergic system, nor conclusive evidence of MDMA serotonergic neurotoxicity has been demonstrated in humans, so far). The serotonergic projections, the primary targets of MDMA's effects in the mammalian brain, originate from the raphe nuclei in the brain stem. Dorsal and median raphe nuclei innervate upper brain structures, including the frontal cortical regions and the hippocampus. The frontal cortex plays major roles in risk evaluation, executive functioning, and working memory, and the hippocampus has a pivotal role in contextual and hereby spatial memory formation.Thus all of the latter regions are candidates for long-run functional consequences caused by MDMA. Nuclear neuroimaging studies have found evidence of reduced 5-HT reuptake transporters across a variety of brain regions within the serotonergic J o u r n a l P r e -p r o o f system, including the temporal cortex). The profile of learning and memory deficits suggest that ecstasy users have particular difficulty with encoding of new material, with relatively spared consolidation and perhaps mild impairment in retrieval.
Although many findings point to DA as a major player in stimulating, and enhancing the properties of MDMA, as well as in its many acute toxic effects such as oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, microglial activation, mitochondrial dysfunction, and endoplasmic reticulum stress). Research on the involvement of the dopaminergic system following long-term MDMA use is still very poor). This may be because MDMA is more prone to serotonin (SERT) transporters than DA (DAT) transporters, and it has been shown that 5-HT neurons are currently targeted for ecstasy, whereas dopaminergic neurons are resistance. Nervous adaptation is one of the factors that leads to drug use into drug abuse that forces a person to use it in an uncontrollable on way who is unable to avoid using it. It is well established that the first important step in addiction is to increase DA neurotransmission. Taking the drug with positive effects on the ventral tegmental area that project towards ventral striatum (nucleus accumbens, which plays a role J o u r n a l P r e -p r o o f in reward system, frontal cortex (involved in the attribution of bulge and executive function), amygdala (involved in emotional responses) and the hippocampus (which involved in long-term memory) activate the mesolimbic system and strengthen the frequent use of the drug and reinforce the connection between the stimuli associated with the drug and the drug booster. Adult rats exposed to MDMA multiple injections have been shown a significant reduction in dopamine cell body and terminals, which by decreasing the dopamine transporter against immunity, decreased dopamine-based secretion and defects in memory formation and recognition processes. In this case, both chronic and acute consumption are important. Meller et al showed that acute MDMA oral administration caused a decrease in striatal DA content. Another studies showed that repeated administration of MDMA in mice decreased the level of DA in substantia nigra. In confirmation of previous studies, daily consumption of low dose MDMA for 10 days in juvenile rats lead to neurotoxic injuries in DA neurons receptors on terminals of them, decrease the mesolimbic inside the body, sensitivity and behavioral disorders, learning and memory in adulthood. MDMA is generally a potent booster of dopamine and serotonin levels. For example, one study showed that injecting 10 mg of ecstasy into mice increased cerebral dopamine levels by 86% and cerebral serotonin levels J o u r n a l P r e -p r o o f by 123%). Other evidence suggests that the tendency and potential neurochemical sensitivity of ecstasy to dopamine, in addition to humans, is very high in several species, including mice, guinea pigs, and monkeys. In addition, it has been shown that MDMA abuse, increase extracellular dopamine levels in the nucleus accumbens of mice who pre-treat with MDMA for 12 days when compared to mice receiving a single dose. In this regard, the role of receptors is important. Ecstasy cross the blood-brain barrier and dominate dopamine / serotonin receptors. In this pathway, the receptors in the midbrain are commanded, and by activating the reward pathway and creating long-term adaptation to neural circuits, it eventually leads to addiction). This pathway is also true for serotonin receptors, however most of the activity of serotonin neurons is in the forebrain. Using fiber photometry of Ca2 + signals, Chao Wei showed that MDMA strongly alters the activity of dopaminergic neurons in the ventral tegmental region(VTA) and serotonergic neurons in the dorsal raphe nucleus(DRN) in rats). The question is whether long-term activation of dopaminergic neurons causes function self-administration or not? It seems the answer to this question is to be a reduction in calcium signals for both serotonin and dopamine receptors. However, J o u r n a l P r e -p r o o f MDMA could not produce any clear effects on the short-term response of either VTA dopamine neurons or DRN serotonin neurons to repetitive infusions. There are four possible mechanisms in this regard: 1) Dopamine and serotonin are released as soon as they are exposed to the drug by an action-independent pathway. In fact, cholinergic receptors release dopamine, independent of their action potential. 2) When exposed to MDMA and cocaine, most neurons are severely inhibited, but a minority of neurons are activated to maintain extracellular dopamine and serotonin homeostasis(Mejias-Aponte,. 3) Auto-inhibition of these neurons occurs following re-absorption of dopamine and serotonin. 4) Without re-absorption by specific carriers, dopamine and serotonin cannot be metabolized effectively and remain for longer. Our previous studies showed that chronic administration of MDMA in low doses activates the dopaminergic system and increases dopamine receptors, especially receptor D1 compared to D4 and D5, as well as memory and learning disorders (shuttle box). Histological examinations showed that these disorders were caused by damage to the memory and learning center, the neurons in the CA1 and CA3 regions of the hippocampus. The moderate doses administration of MDMA had the same results, but it is interesting that in high doses, due to neuronal resistance to J o u r n a l P r e -p r o o f damage and activation of possible adaptation pathways, neither hyperactivity of the dopaminergic system and increased expression of dopamine receptors nor memory impairments were observedAdministration of MDMA induces a cytosolic increase in dopamine, which is metabolized and self-oxidized, producing Reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radicals, DA quinones, superoxide anions, and hydrogen oxygen species that themselves produce oxidative stress and lead to mitochondrial dysfunction and dopaminergic terminal damage. After the MDMA consumption, the inhibition of mitochondrial complex 1 can be a source of free radicals responsible for oxidative stress and the resulting neurotoxicity of this drug in mice. In a large group of animals, MDMA causes hyperthermia, decreased striatal dopamine content and TH-and DAT-immunoreactivity and increased striatal GFAP and Mac-1 expression as well as iNOS and interleukin 15 at 1 and 7 days after drug exposure. Indeed, inactivation of D2-receptor prevents what is mentioned above in the brain. Therefore, the presence of D2-receptor is necessary to create ecstasy-induced neurotoxicity. The term of toxicity here refers to long-term structural and functional damage during drug use. In parallel, another study confirmed that blockers of D1-receptors not D4-receprors in the animal's brain protect against dopaminergic neurotoxicity following MDMA consumption.
In other words, it prevents the destruction of dopaminergic cells and related metabolites in the striatum. In this way reduction of astrogliosis (GFAP+ cells) is clearly seen). One possible mechanism of neuroprotection against MDMA following inactivation of D1-dopamine receptors is the hypothermic response). In other words, ecstasy increases dopamine receptors in the pre-optic nuclei of the hypothalamus, the area associated with body temperature regulation. Hyperthermia can enhance the neural activity of amphetamines by enhancing DAT function and supporting the production of free radicals and dopamine oxidation in the brain. However, hyperthermia is not always necessary for MDMA-induced dopaminergic neurotoxicity, as hypothermia does not always completely block MDMA neurotoxicity.demonstrated that intra-striatal injection of SCH23390, a D1R antagonist, protects against methamphetamine neurotoxicity with any effect on the hyperthermic response. Blocked D1/D5-dopamine receptors have similar effects which prevent hyperthermia is also provided(Vanattou-Saïfoudine,
Frequent use of MDMA not only increases motor activity but also amplify the effects of MDMA, which seems presence of D2-dopamine receptors to be critical.
The molecular targets of MDMA are the transporter (uptake) sites for serotonine and dopamine. Whilst these transporter sites are located predominantly on presynaptic serotonergic and dopaminergic neurons, respectively, there is now J o u r n a l P r e -p r o o f ample evidence that cells of the immune system also express transporters for both of these neurotransmitters. In mice, MDMA induces selective neurotoxic damage to dopaminergic terminals, yielding a decrease in tyrosine hydroxylase activity, dopamine concentration, and dopamine transporter). In the other experimental animals such as rats and primates, MDMA neurotoxicity may last from months up to years, such as motor dysfunction secondary to dopamine depletion. Several findings have suggested that neuro-inflammation may be one of the pathogenic factors responsible for neurodegenerative processes) and elevated levels of glia-generated reactive species (e.g., nitric oxide, superoxide, cytokines) have been shown to correlate with neurodegeneration induced by amphetamine-related drugs. Recent studies have demonstrated that glial activation participates in the events that induce neuronal damage, since chronic neuro-inflammation elevates the levels of glia-derived cytokines that exert neurotoxic effects on vulnerable dopaminergic neurons. This mechanism provides support for a causal relationship between MDMA-induced neurotoxicity and neuro-inflammation. Several preclinical studies in rats and mice have demonstrated that MDMA elicits J o u r n a l P r e -p r o o f astroglial and microglial activation in the mouse striatum, as well as in the cortex) and hippocampus(Lopez-Rodriguez, Llorente-
Microglial activation rapidly occurs after MDMA administration, thus, MDMA can trigger the release of a number of pro-inflammatory cytokines that lead to glial dysfunction as well as neuronal death. Indeed, it has been shown that inhibition of microglial activation by minocycline protects against the neurotoxic effects of amphetamine derivatives, including methamphetamine (METH). METH increases reactive microglia in the striatum, hippocampus, cortex, and substantia nigra, peaking one day after administration. METH also increases glial fibrillary acidic protein (GFAP) immunoreactivity in the striatum(Ares-Santos,) and in indusium griseum. GFAP is a marker of astrogliosis (gliosis). Reactive gliosis is considered a universal reaction to injury in the CNS and is used as a sensitive marker in neuronal damage. Given that suppression of neuro-inflammation mediated by microglia activation may help preventer reverse, neurodegenerative diseases, a number of drugs such as J o u r n a l P r e -p r o o f nicotine, resveratrol and curcumin have been tested over the years that act on different parts of the inflammatory pathways.
Adenosine is an endogenous signaling molecule that engages cell surface adenosine receptors to regulate numerous physiological and pathological processes. Adenosine, is produced in response to metabolic stress and cell damage, and elevations in extracellular adenosine are found in conditions of ischemia, hypoxia, inflammation, and trauma. Adenosine acts in the central nervous system as a neuromodulator, with dopamine (DA) neurotransmission being one of its targets. Four adenosine receptor subtypes, A1, A2A, A2B and A3, have been defined by pharmacological and molecular biological approaches. These receptors belong to the superfamily of G-protein-coupled receptors. Receptor subtypes are distinguished based on their affinity for adenosine, pharmacological profiles, Gprotein coupling and signaling pathways, and genetic sequence. Specifically, as for the presence of each AR subtype in CNS, the A1 receptor (A1R) is mainly present in the cortex, hippocampus, cerebellum, nerve terminals, spinal cord, and glia. This wide range of locations reflects the multitude of physiological effects orchestrated by it, including inhibition of neurotransmitter release, anticonvulsant and anxiolytic J o u r n a l P r e -p r o o f effects, sedation, analgesia and sleep regulation. A2A adenosine receptors (A2AR) were originally shown to be abundant in discrete brain areas such as striatum, basal ganglia, hippocampus and cortex. A2B receptors (A2BR) are present in the astrocytes, neurons, and microglia, but their role in the CNS is less well characterized in comparison to the other AR subtypes in the CNS. Both A2AR and A2BR can promote adenylyl cyclase and cause increased intracellular cAMP, which promotes glycogenolysis and increases the energy supply of neurons). A3 receptors (A3R) is widely distributed throughout the brain but has the lowest density compared with the other receptors, being mainly distributed in the hippocampus and cerebellum, signaling pathways including adenylyl cyclase inhibition. A3R has different effects at different doses and administration times. Activation of A3R has both neuroprotective and neurotraumatic effects. A1R and A3ARs inhibit adenylate cyclase activity and decrease cAMP production while A2A and A2BRs exert an increase of cAMP accumulation. The most evident effect of adenosine in neuronal circuits of adult mammals is to selectively depress excitatory transmission. This occurs through the activation of J o u r n a l P r e -p r o o f A1R, which are located both presynaptically, postsynaptically and nonsynaptically. A2AR are selective controllers of adaptive changes of synaptic efficiency. This is in accordance with the ability of A2AR to enhance the evoked release of glutamate in different brain areas). A2AR also act as fine tuners of other neuromodulator systems. Thus, A2AR act as a hub, switching pre-synaptic modulation from inhibitory to facilitator. A2AR can affect glial reactivity and control neuroinflammatory processes. A2AR are also located in astrocytesand microglia cellswhere they control Na+/K+-ATPase) and the uptake of glutamateas well as the production of pro-inflammatory cytokines. A2AR are also located in endothelial cells of brain capillaries, where they play an important role in controlling brain vascular function. It is also important to mention that both A1R and A2AR can affect brain metabolism. It is still unclear to what extent this metabolic control in brain tissue but this ability of adenosine receptors to control metabolic activity is expected to play a potentially relevant J o u r n a l P r e -p r o o f role in the control of both physiological and pathological brain adaptive changes, which are highly dependent on adequate metabolic support.
A large number and variety of mediators are involved in inflammation. Adenosine is a potent endogenous anti-inflammatory agent that regulates the function of inflammatory cells via interaction with specific receptors expressed on these cells. Adenosine released from stressed cells can act as a physiological inhibitor of inflammation. Activation of A2AR, A2BR and A3Rs is known to have anti-inflammatory effects in part due to inhibition of the release of proinflammatory cytokines. The antiinflammatory role of the A2AR has been extensively studied and confirmed in multiple animal models. However, the pro-or anti-inflammatory roles of both A2BR and A3Rs are still controversial. Numerous investigations in cellular and animal model systems have provided evidence that A2AR signaling pathways are active in limiting inflammation and tissue injury. Adenosine, acting primarily at A2A receptors, has long been known to be a potent vasodilator and this is the basis for use of adenosine and A2AR agonists for pharmacologic stress testing. Thus, it is likely adenosine release at inflamed sites J o u r n a l P r e -p r o o f contributes to the erythema (rubor) and resulting heat loss (calor) associated with inflammation. It was initially thought that most extracellular adenosine came from intracellular adenosine as a product of ATP, due to an increased metabolic demand of the cell. Neutrophils are recruited to inflamed sites by a combination of chemokines and adhesive interactions between leukocytes and the vascular endothelium. Adenosine receptor stimulation diminishes neutrophil adhesion to the endothelium by inhibiting both selectin and integrin mediated adhesive events. It has been well documented that adenosine and its receptors are able to suppress elevated levels of proinflammatory cytokines such as tumor necrosis factor 𝛼 (TNF-𝛼) and interleukin 𝛽 (IL-𝛽) released in the most common musculoskeletal diseases and rheumatoid. Ohta et al studies in A2AAR knockout mice showed that this receptor plays an important role in limiting the degree of inflammatory mediator production and tissue injury in response to challenges with concanavalin A or endotoxin subthreshold doses of these agents that caused minimal responses in wildtype mice led to extensive inflammatory mediator production, tissue damage and death in A2AR knockout mice.
The ability of A2AR activation to suppress Th1 cytokine and chemokine expression by immune cells is likely the dominant mechanism involved. For example, A2AR activation can attenuate IL-12, INFγ and TNF-α production from important immunomodulatory cells such as monocytes, dendritic cellsand T cells. Adenosine receptors and neuroinflammation: Recent studies suggest that astroglia plays a very important role in the production of extracellular adenosine. Astrocyte activation causes it to be release glutamate and ATP, which can then be converted to adenosine by means of ectonucleotidase. Also the neuromodulator adenosine regulates immune activation and neuronal survival through specific G-proteincoupled receptors expressed on macrophages and neurons. The main adenosine receptors involved in the neuroinflammation modulation are A1R and A2AR. Evidence suggests that A1R activation produces a neuroprotective effect and A2ARs block prevents neuroinflammation. In the CNS, the A1R is highly expressed on microglia/macrophages and neurons but not on infiltrating lymphocytes, although its effects on neuroinflammation remain uncertain but many studies showed that A1R is a critical endogenous physiological regulator in neurons and it may be potential therapeutic target in neuroinflammation(Johnston,
Silva. Evidence suggests that A1R activation produces a neuroprotective effect. In A1R knockout mice, an increase in neuroinflammation and microglia activity has been seen. Also A1R knockout animals exhibited severe demyelination and axonal injury, involving the activation of macrophages and microglial cells). In physiological or pathological conditions, A1R activation, induced the release of nerve growth factor (NGF) .Nerve growth factor plays a neuroprotective role in CNS, it is secreted mainly by astrocytes and microglia, and is related to A1R and A2AR, respectively) . Tsutsui et al showed that chronic treatment with caffeine, a nonselective competitive A1R and A2AR antagonist increased the A1R expression in macrophage/microglia during MS, with an ensuing attenuation of disease, which was further enhanced by concomitant treatment with the A1R agonist). The A2AR, in physiological conditions, is highly expressed in striatal neurons and less in glial cells). A2AR expression is very sensitive to changes in the concentrations of endogenous and exogenous factors involved in inflammation. In rats subjected to haemorrhagic stroke, administration of A2AR agonist (CGS21680) to the striatum J o u r n a l P r e -p r o o f inhibited TNF-α production and neutrophil infiltration and reduced cell death. Meanwhile, the improved neurological outcome observed in rabbits treated with ATL146e (A2AR agonist) following spinal cord trauma was associated with reduced infiltration of inflammatory cells. Another studies in animal models of Parkinson's disease) and traumatic brain injurysuggest that A2AR blockade control microglial activation. Moreover, A2AR stimulation enhances the proliferation and activation of astrocytes secondary to a nervous injury , while the A2AR antagonists 1,3-dipropyl-7-methylxanthine (DPMX) and SCH58261 have opposite effectsAlthough the proliferation and/or apoptosis of microglia are regulated by several adenosine receptors, the secretor activity of these cells appears to be stimulated by A2ARand the fact that A 2A receptors are expressed on most cells of the immune system is necessary to its anti-inflammatory effects). Several studies have shown that the. Thus, the anti-inflammatory properties of these receptors are due, at least in part, to the prevention of the activation of effector cells of the immune system like neutrophils and glia). Among the four adenosine receptors, A2BR are less well known and their role in the CNS is less well characterized in comparison to the other AR subtypes. A low level of their expression has been detected in the astrocytes, neurons, and microglia. Yang et al reported that A2BR-null mice present increase of proinflammatory cytokine levels, such as TNF-α, and leukocyte migration in response to inflammation. There is growing evidence that A2BR can also become operational in regulating macrophage function. In opposition to such data, Nabbi-Schroeter et al suggested that caffeine, may protect against neuronal degeneration by blocking A2AR. They observed that the A2BR antagonist has a certain protective effect against Alzheimer(Nabbi-Schroeter, Elmenhorst et al. 2018). Finally, A3R, are present in hippocampus, cortex, thalamus, pial and intracerebral arteries and glia. Studies have shown that A3R has different effects at different doses. A3R have both neurotraumatic and J o u r n a l P r e -p r o o f neuroprotective results. However, the pro-or anti-inflammatory roles of A3Rs are still controversial.. Adenosine receptors and addiction: Adenosine, an ubiquitous endogenous nucleoside, has been implicated in the reward-related behavior, and represents a novel and interesting target to interfere with it, as a consequence of its modulatory function on neurotransmission exerted by DA, glutamate and acetylcholine. Interestingly, adenosine levels are modified following acute or chronic consumption of drugs of abuse and psychostimulants. Building on this rationale, adenosine receptors is particularly important when we are studying the effects of drugs of abuse, for reasons that have been extensively reviewed previously.
The process of addiction depends on an increase in DA neurotransmission in the striatum and an activation of its receptors. The DA receptors most involved are of the D2 subtype, and their induction of relapse as a consequence of chronic drug administration. MDMA induces its effects by indirectly increasing DA levels and directly activating D2 receptors, thus J o u r n a l P r e -p r o o f enhancing dopaminergic signaling. Adenosine acts in the central nervous system as a neuromodulator, with DA neurotransmission being one of its targets. The modulation of dopaminergic activity is mediated by two subtypes of AR, being the antagonist of DA receptors, A1R co-localize with D1 receptors, and A2AR with D2 receptors. A2AR are highly expressed in the striatum and several studies have demonstrated the existence of interaction between A2AR and D2 receptors, co-localized in discrete neurons located at the striatal complex, a key brain nucleus for the reward circuitry. At the membrane level, A2AR activation put on a balancing effect to D2 receptor stimulation, in the way that it's stimulation has been reported to decrease D2 receptor affinity.
In addition to dopamine, a role for 5-HT in MDMA rewarding effects has also been described. 5-HT release is regulated through A1R and A2AR, exerting opposite effects on 5-HT release. Thus stimulation of A1R decreases extracellular 5-HT concentrations, whereas A2AR stimulation increases extracellular 5-HT. Mossner et al showed that there is an adaptive increase of A1R and a decrease of A2AR in 5HT J o u r n a l P r e -p r o o f knockout miceSimilarly, A1R blockade was shown to increase hippocampal 5-HT release(130). Several studies reported that adenosine receptor antagonists markedly enhanced MDMA-induced DA and 5-HT release in the mouse striatum, but the potency of their effect was different. These data indicate that DA and 5-HT nerve terminals are under tonic influence of A1R and A2AR. It seems that, PKA (protein kinase activity) plays an important role in the interaction between A1R and A2AR on hippocampal serotonin release.
The process of addiction depends on an increase in DA neurotransmission in the striatum and an activation of its receptors. The dopamine D2 receptor appears to play a pivotal role in the mediation of drug abuse. Adenosine receptors interact in an antagonistic way with DA receptors. Dopamine D2 and A2AR have been shown to interact in an opposing manner on several levels. D2 receptor activation inhibits A2AR agonist-activated cAMP accumulation. The bulk of evidence to date explained the adenosine involvement in opiate reward centers on opiate withdrawal. J o u r n a l P r e -p r o o f Adenosine, via A2ARs, modulates behaviors associated with acute and chronic exposure to caffeine, cannabinoids), nicotine, alcohol), and MDMA. In rats trained to self-administer heroin, the administration of A2AR antagonists eliminated reinstatement. It was reported that when the A3R was genetically deleted, the resultant mice were much more sensitive to the toxic actions of metamphetamines, including caspase 3 and TNF-α. Microinfusions of A1R agonist (CPA) in the accumbance nucleous of Sprague-Dawley rats inhibited cocaine seeking behavior. In human studies, blockade of A2AR in cocaine-dependent volunteers caused increased brain activation in the orbitofrontal cortex, insula, and superior and middle temporal pole, as measured by fMRI). Kobayashi et al showed that in methamphetamine users, A2RA gene could be a vulnerability factor for drug dependence especially in females. J o u r n a l P r e -p r o o f Conversely, several authors have shown that adenosine antagonists could reduce symptoms associated with precipitated opiate withdrawal). It has been reported that adenosine signaling pathways could be considered a new There is no consensus regarding the effects of A2AR in the neuroinflammation; some studies suggest proinflammatory effects, while others suggest antiinflammatory effects and these opposing roles depend on the timing and J o u r n a l P r e -p r o o f concentration. Contradiction of adenosine receptor agonists and antagonists behavior to treat neuroinflammation suggests that factors such as dosage, drug delivery method and pharmacological relationship between adenosine and dopamine receptors as they influence glutamate release should be considered in the treatment strategies. Acute or chronic toxicity of the drug is also one of the influential factors. Microglial activation can rapidly occur after certain types of CNS insult, being considered a selective pharmacological marker for amphetamine-induced nerve terminal damage.Once microglial cells are activated, secrete proinflammatory cytokines, prostaglandins and nitric oxide , that have been involved in MDMA-induced neurotoxicity). One important mechanism by which A2AR antagonists can contribute to neuroprotection is through the inhibition of the pathological activation of glial cells. Microglial activation represents a response to direct damage by the neurotoxic amphetamines, and is also part of the cascade leading to neuronal damage. In fact, microglial cells express A2AR, which seem to play a role in their secretory and proinflammatory activity). Consequently, blockade of A2AR decreases release of proinflammatory prostaglandins and toxic cytokines, and free radical formation.
There are major challenges in developing adenosine receptors for clinical applications such as their widespread signaling in physiological and pathophysiological conditions. Also this varies from person to person. This broad distribution makes it difficult to achieving tissue selectivity. Another challenge relates to the difficulty in distinguishing between the various sources of extracellular adenosine under physiological and pathological conditions. In some cases, repeated or prolonged exposure to adenosine receptor ligands leads to the rapid development of tolerance.
It has been suggested that one important mechanism by which adenosine receptors can contribute to neuroprotection is through the inhibition of the pathological activation of glial cells. There have not been many studies on the effects of adenosine receptors on acute and chronic complications reported by MDMA and we need more studies to complete the information. Finally, the current status of knowledge on the potential interest of the adenosine neuromodulation system is rather exciting but due to the dispersion and diffuse effects of adenosinergic system, use it as a medicine in drug abuse is like a doubleedged swors and further investigation are needed for molecular mechanisms triggered by adenosine receptors activation.
J o u r n a l P r e -p r o o f
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Young, M. B., Norrholm, S. D., Khoury, L. M. et al. · Psychopharmacology (2017)