MDMA related neuroinflammation and adenosine receptors

This review (2022) explores the cellular mechanisms involved in MDMA neuroinflammatory effects. The protective effects of adenosine receptors are also discussed.

Abstract

“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.”

Authors: Fatemeh Kermanian, Masoumeh Seghatoleslam & Simin Mahakizadeh

Authors Highlights

• Adenosine receptors appear to have great potential for treating side effects of MDMA.

• Adenosine receptors could decrease microglial activation in neuroinflammation conditions.

• MDMA and adenosine receptors have opposite effects on dopaminergic and serotonergic systems.

Summary

MDMA, a world-wide abused psychostimulant, has neurotoxic effects on dopaminergic and serotonergic neurons, and adenosine acts as a neuromodulator of dopamine neurotransmission. Adenosine receptors may protect against these effects.

The popular recreational drug, “ecstasy”, is a phenethylamine structurally similar to both amphetamine and mescaline, a hallucinogenic and intoxicating compound present in mescal buttons from the peyote cactus. It has some false positive acute psychological effects, including feelings of euphoria, elevated self-confidence and boosted sensory watchfulness.

After acute exposure to MDMD, dopamine diffusion increases in the abdominal tegmental region, the prefrontal cortex, the amygdala, and the hippocampus, which reinforces repeated use of the drug, which leads to addiction.

MDMA acts as a substrate for various types of vesicular carrier monoamine transporter proteins and thus releases serotonin (5HT), dopamine (DA) and norepinephrine. MDMA also influences various structures of the brain, including the cortex, hippocampus and limbic system, which play important roles in learning, memory, long-term information storage and spatial reasoning.

MDMA use has increased significantly in the United States and Australia, with nearly one million people having used ecstasy at some time during their lives and 3% of the adult population having used it in the past year. The European Union Drug Administration has revealed that 0.5 to 3% of European adult society are addicted to ecstasy, with the highest intake among young people aged 15 to 16.

In Southeast Asia, ecstasy use is typically restricted to youth from higher socio-economic class, however, there have been reports of ecstasy use among other population groups. In Middle Eastern countries, the use of amphetamines has increased dramatically over the past few years.

MDMA consumption has been shown to cause loss of shyness and impulsivity, negativity and social connection in proximal outcome, hyperthermia and neurotoxicity, neuroinflammation, and memory and cognitive impairment. The hippocampus, amygdala, and frontal cortex are strongly affected by ecstasy consumption.

The hippocampus is part of the limbic system, which contains serotonergic receptors, and is responsible for memory processing, emotion control, judgment, love and motivation. There are some documents that show that not only MDMA disrupts function of mentioned areas but also the occipital area is particularly impressed by ecstasy. The hippocampus is the main area in cognitive activities, especially memory, and use of amphetamine derivate can injure these abilities.

Researchers believe that serotonin depletion in the hippocampus and prefrontal cortex causes deficiency in normal function of these regions, which are related to memory and personality. Serotonin is also involved in many important physiological functions, including foo d intake, reproduction, immunity, nervous function, and anti-stress responses.

MDMA abuse can potentially result in absolute or relative reductions in CNS gray matter via transmitter-mediated toxicity, vascular ischemia or hemorrhage, or loss of neurotrophic effects. Serotonergic syndrome is caused by the excessive discharge of serotonin in the brain tissue.

Drugs that contain amphetamine compounds, such as ecstasy, can easily increase 5-HT that activates both synaptic and extra-synaptic 5-HT1A receptors, which can lead to socioaffective behaviors, symptoms of mood dysregulation, and seizures.

MDMA has been shown to decrease long term 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. MDMA use may also be associated with reduced SERT density in several brain regions.

ecstasy/MDMA users demonstrate memory and learning deficits, which can persist after prolonged abstinence. These memory deficits are not due to involvement of the serotonergic system, nor has conclusive evidence of MDMA serotonergic neurotoxicity been demonstrated in humans, so far.

Ecstasy users have difficulty encoding new material, with spared consolidation and mild impairment in retrieval. MDMA has many acute toxic effects, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, and microglial activation. Research on the involvement of the dopaminergic system following long-term MDMA use is still very poor. However, it is well established that the first important step in addiction is to increase DA neurotransmission.

The reward system, amygdala, and hippocampus are activated by drugs, which strengthen the connection between the stimuli and the drug. MDMA is a potent booster of dopamine and serotonin levels, and chronic and acute consumption are important. Chronic consumption of MDMA leads to neurotoxic injuries in DA neurons, decrease the level of DA in substantia nigra, and decrease mesolimbic inside the body, sensitivity and behavioral disorders, learning and memory in adulthood.

MDMA abuse increases dopamine levels in the nucleus accumbens of mice who pre-treat with MDMA for 12 days, and this increases the risk of addiction. However, the long-term activation of dopaminergic neurons may not cause addiction.

MDMA could not produce any clear effects on the short-term response of either VTA dopamine neurons or DRN serotonin neurons to repetitive infusions. This may be due to an action-independent pathway, auto-inhibition, or re-absorption of dopamine and serotonin by specific carriers.

MDMA administration induces a cytosolic increase in dopamine, which is metabolized and self-oxidized, producing Reactive oxygen species (ROS) that cause oxidative stress and lead to mitochondrial dysfunction and dopaminergic terminal damage. The presence of D2-receptor is necessary to create ecstasy-induced neurotoxicity.

MDMA increases motor activity and amplifies the effects of MDMA by increasing dopamine receptors in the pre-optic nuclei of the hypothalamus, which is associated with body temperature regulation. Hypothermia can enhance the neural activity of amphetamines by enhancing DAT function and supporting the production of free radicals and dopamine oxidation in the brain.

MDMA affects both D1 and D2 receptors, and both are involved in the acute motor effects of MDMA as well as the maintenance of self-administration. However, the role of D1 and D2 receptor mechanisms in the development of MDMA sensitivity is different.

MDMA induces neurotoxic damage to dopaminergic terminals in mice, which leads to a decrease in tyrosine hydroxylase activity, dopamine concentration, and dopamine transporter. Glial activation participates in the events that induce neuronal damage, which provides support for a causal relationship between MDMA-induced neurotoxicity and neuro-inflammation.

METH increases reactive microglia in the striatum, hippocampus, cortex, and substantia nigra, and GFAP immunoreactivity in the striatum and indusium griseum, and may be a sensitive marker in neuronal damage. Suppression of neuro-inflammation mediated by microglia activation may help prevent and reverse neurodegenerative diseases.

Adenosine is an endogenous signaling molecule that engages cell surface adenosine receptors to regulate numerous physiological and pathological processes. The A1 receptor (A1R) is mainly present in the cortex, hippocampus, cerebellum, nerve terminals, spinal cord, and glia.

Adenosine has several effects in the brain, including sedation, analgesia and sleep regulation. Adenosine acts through several receptors, including A2A and A2B, which promote adenylyl cyclase and increase intracellular cAMP, which promotes glycogenolysis and increases the energy supply of neurons.

A2AR are selective controllers of adaptive changes of synaptic efficiency, and can also act as fine tuners of other neuromodulator systems. They are also located in astrocytes and microglia cells, where they control Na+/K+-ATPase and the uptake of glutamate, as well as the production of pro-inflammatory cytokines. Adenosine receptors are located in endothelial cells of brain capillaries and can affect brain metabolism. They may play a role in the control of both physiological and pathological brain adaptive changes.

Adenosine, acting primarily at A2A receptors, is a potent endogenous anti-inflammatory agent that regulates the function of inflammatory cells via interaction with specific receptors expressed on these cells. Adenosine release at inflamed sites is likely to be a physiological inhibitor of inflammation.

Adenosine contributes to the erythema and resulting heat loss associated with inflammation. Adenosine and its receptors are able to suppress elevated levels of proinflammatory cytokines such as tumor necrosis factor and interleukin released in the most common musculoskeletal diseases and rheumatoid.

A2AR activation can attenuate IL-12, INF and TNF-production by important immunomodulatory cells such as monocytes, dendritic cells and T cells, and can also regulate immune activation and neuronal survival through specific G-protein coupled receptors expressed on macrophages and neurons.

Evidence suggests that A1R activation produces a neuroprotective effect. A1R knockout mice exhibit an increase in neuroinflammation and microglia activity, and A1R activation induces the release of nerve growth factor, which plays a neuroprotective role in the CNS.

The A2AR signaling in suppressing inflammation is related to the increase of cAMP levels and reduction of the release of inflammatory mediators such as IL-12, INF, TNF-18 , and IL-4 from important immunomodulatory cells such as neutrophils, monocytes, dendritic cells and T lymphocytes which have well -known as immunosuppressive effects.

Adenosine receptor A2BR is less well known and its role in the CNS is less well characterized in comparison to the other AR subtypes. However, caffeine may protect against neuronal degeneration by blocking A2BR. Adenosine receptors (A3R) are present in the hippocampus, cortex, thalamus, pial and intracerebral arteries and glia. They have both neurotraumatic and Journal Pre-proof 1 neuroprotective results.

Adenosine, an endogenous nucleoside, has been implicated in reward-related behavior, and may be a novel target to interfere with it. The D2 subtype of dopamine receptors is most involved in addiction, and MDMA induces its effects by indirectly increasing DA levels and directly activating D2 receptors.

Adenosine acts in the central nervous system as a neuromodulator, with dopamine being one of its targets. Adenosine is also regulated by serotonin receptors, with A1R and A2AR exerting opposite effects on 5-HT release.

Knockout mice and A1R blockade increased hippocampal 5-HT release, and A1R and A2AR interact in an antagonistic way on several levels, including DA neurotransmission, neuroinflammation, and adenosine receptors.

Adenosine, via A2ARs, modulates behaviors associated with acute and chronic exposure to caffeine, cannabinoids, nicotine, alcohol, and MDMA. A2RA gene could be a vulnerability factor for drug dependence especially in females.

Adenosine signaling pathways could be a new target for the management of MDMA consumption, as they are involved in the regulation of dopamine and glutamate release, glutamate clearance by astrocytes, inflammatory reactivity by microglia, vascular resistance or a direct control of calcium entry or cell cycling in neurons.

The A2AR and D2 receptors may be linked to each other and form heteromers, causing antagonistic interactions. Astrocytes are the main source of adenosine in synapses and play a regulatory role in CNS, regulating the content of adenosine in synapses and coupling neuronal function to the cerebral microvasculature.

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.

Adenosine receptors are widespread in physiological and pathophysiological conditions, and their widespread signaling makes it difficult to achieve tissue selectivity. It has been suggested that adenosine receptors can contribute to neuroprotection through the inhibition of the pathological activation of glial cells.