The purinergic system is a complex means of intercellular communication, composed of adenosine nucleotides, adenosine nucleoside, respective receptors and enzymes. Initially seen only as an energy molecule, ATP has been highlighted in the literature as the protagonist of several physiological processes, including inflammatory ones (Cheffer et al. 2018; Bartoli et al. 2020a). From this perspective, considering a neuroinflammatory and oxidized scenario, it is necessary to recognize the expression of receptors and the actions that high levels of extracellular ATP can trigger (Savio et al. 2021) (Tables 1, 2).

The purinergic system acts directly on mechanisms related to neurotransmission and neuromodulation through its receptors (Bartoli et al. 2020b) and thus plays an important role in the regulation of psychological functions and consequently in the pathophysiology of disorders such as depression (Bartoli et al. 2020a), and thus it is essential to recognize its mechanisms and processes to elucidate possible treatment targets for depression. Also, extracellular ATP, one of the main components of the purinergic system, is also related to the regulation of the activities of microglia and astrocytes, which has already been evidenced as one of the components of the development of depression, and therefore, dysregulation of this system lead to changes in the physiology of neurotransmitters and hormones, also involving the HPA axis (Bartoli et al. 2020a).

With regard to purinergic receptors, they are differentiated into two families: P1 and P2. The P1 are subdivided into A1, A2A, A2B and A3, with the A1 and A3 being activated by adenosine (ADO), and responsible for inhibiting the production of cAMP, while the A2A and A2B stimulate its production (Burnstock 2018). On the other hand, P2 receptors are classified into P2X ionotropic and P2Y metabotropic, and are sensitive to the di (ADP) and triphosphate (ATP) form (Burnstock 2018). Regarding the role of P1 receptors in the central nervous system, A1 and A2A have fundamental functions for the functioning of adenosine in the brain, the first being better distributed in brain tissue while the second is highly expressed in neurons. However, A2B and A3 have limited actions in this regard (Bartoli et al. 2020a).

Furthermore, A1 and A2A receptors are targets of treatment for several psychiatric diseases, as they control synaptic plasticity and release of glutamate, dopamine and GABA, among other neurotransmitters, as well as A3 that regulates the serotonergic and glutamatergic systems (Cheffer et al. 2018). Overall, according to Bartoli et al. (2020a), adenosine induces a negative feedback to the excitatory activities of glutamatergic synapses, acting in neuromodulatory and neuroprotective inhibition. From this, we have that the A1 and A2A receptors exert complementary actions and therefore the release of neurotransmitters depends on a balance between them, since the presynaptic A1 has an inhibitory function in relation to the release of several neurotransmitters, while the Postsynaptic agents reduce neuronal signaling through potassium channels. A2A, on the other hand, seem to be related to the regulation of synaptic plasticity (Bartoli et al. 2020a).

Thus, a non-selective activation of ADO receptors increases the recurrence of depressive symptoms while a selective A2A antagonism or a deletion of these receptors seems to reduce these symptoms. Furthermore, chronic stress can reduce the concentration of available adenosine, thus activating A1 receptors, which as already mentioned, decreases the concentration of available serotonin (Bartoli et al. 2020a), which is related to the development of depressive symptoms (Carlessi et al. 2021) in addition to being related to COVID-19 since it leads to the development of chronic stress in some situations.

Furthermore, depression may also be associated with decreased functionality of astrocytes, which leads to a decreased activation of adenosine 1 inhibitory receptors in neurons, which therefore increases the functioning of A2A receptors, which are associated with neuroplasticity and neuroinflammation it is also associated with suicidal ideation and attempts (Bartoli et al. 2020a), since there is a decrease in adenosine deaminase activity, generating a reduction in adenosine turnover, consequently leading to a decrease in uric acid, which has already been associated to depressive disorders (Bartoli et al. 2020b).

The purinergic system is related to depression, among the factors mentioned, also because the mechanisms of the HPA axis and hormone release are controlled by adenosine receptors, and both A2A and A2B generate an increase in adrenal corticosterone synthesis, in addition to altering the functioning of glucocorticoids (Chen et al. 2010). In addition, adenosine and ATP regulate the activities of microglia and astrocytes, especially with regard to communication between them (Cheffer et al. 2018), which is essential to establish a link with the development of depression, since that the hypoactivity of astrocytes and the hyperactivation of glia were already mentioned as fundamental factors in the development of depressive disorders (Carlessi et al. 2021).

Regarding P2 receptors, the most studied receptor linked to depression is P2X7, as it is involved in the modulation of different neurotransmitters and pro-inflammatory activity, and in relation to the latter, it is evident that the feeling of stress can influence the mechanisms of the immune system through this receptor (Bartoli et al. 2020a), and thus these receptors have an important role in relation to the neuropathology of depression and the purinergic system since it is activated by high concentrations of ATP. Furthermore, the activation of P2X7 leads to an activation of microglia and consequent release of a cascade of pro-inflammatory cytokines, mainly interleukin-1beta (Vereczkei et al. 2019), which leads to changes related to synaptic plasticity, neurogenesis and neuroprotection (Cheffer et al. 2018), becoming an important treatment target in depression since it, as mentioned above, also involves important pro-inflammatory processes. Still, in relation to P2 receptors in general, the combination of non-specific P2 receptor antagonists with antidepressants was associated with positive effects (Bartoli et al. 2020a).

From this, recent researches report the success of adenosine administration and the regulation of ATP release in the treatment of depressive illnesses (Illes et al. 2020a; Gomes et al. 2021). As hypothesized to link mitochondrial function with neuroinflammation that leads to depression, dysfunction of exogenous ATP levels can trigger neuropsychiatric diseases. This happens because stress ends up releasing ATP, which stimulates P2X7 receptors that lead to the release of IL-1β (Sharma 2019), this pre-inflammation factor releases CRH and the active form of the inflammasome of NLRP3 in the hippocampus (Illes et al. 2020a). Thus, recent research studies the genetic inhibition of the P2X7R-Pannexin 1 (Panx-1) pore complex, the suppression of active splice variants of the receptor, using both non-selective P2X7Rs antagonists and Brilliant Blue G (BBG), antagonist selective for P2X7R, with a potential use for antidepressant treatments (Illes et al. 2020a).

In analyzes carried out in rodents, in which the P2X7Rs genes were removed, the result showed antidepressant phenotypes, related to mood behavior. In other words, the absence of P2X7R, which could be pharmacologically induced, could act as an antidepressant. An example of pharmacological use is P2X7R Brilliant Blue G, performed in the same genetic suppression research, which neutralized the depressive behavior of mice induced by bacterial endotoxin (Savio et al. 2018).

From a negative perspective of the use of this treatment, studies indicate that ATP blockade and evidence of the use of lower extracellular concentrations do not result in the action of the antagonist. There are problems that hinder the action of this antagonist, in addition to the fact that it only acts at high concentrations of ATP, current research has used rodent receptors as experimental use when investigated in human receptors in vitro, the result was not the same. In addition, P2X7R antagonists do not have easy permeability to the CNS, as they must pass through the blood–brain barrier (Illes et al. 2020a). However, several current researches demonstrate drugs that achieved excellent penetration in the cerebral cortex of rodents, when administered subcutaneously (Illes et al. 2020a). As an example of potent P2X7R antagonists, there is AZ-10606120 (Csölle et al. 2013), JNJ-47965567 and JNJ-42253432 (Illes et al. 2020a).

It is known that stressful situations cause an increase in exogenous ATP in the brain, activating P2X7Rs receptors which then release IL-1β and NLRP3, increasing the levels of glucocorticoids and adrenocorticotropic hormone. While such factors were evidenced in patients with TMD, microglia becomes an important agent and target of studies in this disorder. This is because it participates in the tripartite synapse (which occurs between pre and post ganglion cells and astrocytes) which is regulated according to the levels of ATP, related to its P2X and P2Y receptors (Illes et al. 2020a). Microglia can, therefore, carry out cell proliferation or apoptosis, depending on the receptors and levels of ATP. The P2X7 receptor showed to perform apoptosis even in the absence of ATP, while others such as P2Y1Rs coordinate the migration of microglia and P2Y6Rs guide the phagocytosis of bacteria and cell debris. The P2X7 ends up affecting the microglia through signal transduction pathways leading to neuroinflammation, as the release of cytokines, reactive oxygen and nitrogen species that can generate depressive reactions (Illes et al. 2020a).

In comparison with the monoaminergic proposal for the treatment of depression, the P2X7 receptor can also modulate the release of 5-HT, norepinephrine and glutamate. Even though recent research does not know the exact location of the receptor given the lack of selective drugs to recognize its subtype, there are contradictions between current findings. While there is evidence that P2X7R knockout mice showed high levels of 5-HT in the hippocampus under stressful circumstances, acting in monoaminergic upregulation, as well as evidence from genetically deficient mice in the receptor, there is a decrease in the release of 5-HT in the hippocampus, it can also happen to inhibit 5-HT and noradrenaline, impairing depressive behavior (Ribeiro et al. 2019).

There are also different perspectives regarding the relationship between the receptor and the release of GABA. While research demonstrates that P2X7R stimulation in the hippocampus induces glutamate release, inhibition of the receptors can also release GABA through adenosine hydrolysis. Likewise, in astrocyte cultures, P2X7R reduces the expression of the sodium-dependent glutamate/aspartate transporter (GLAST) decreasing GABA and glutamate uptake in rat experiments. As well as it can affect the formation of nitric oxide according to situations of oxidative stress through the stimulation of P2X7R. From the use of receptor antagonists as antidepressant treatment, there was a decrease in NO in the prefrontal cortex of mice. That is, P2X7R can also increase NO concentrations in the limbic regions of the brain and the use of antagonists can be used as antidepressants (Ribeiro et al. 2019).

For adenosine reception by the purinergic system, there are the P1 family receptors, which have different actions in the regulation of depressive symptoms. While A1Rs have antidepressant and anxiolytic properties, A2ARs have opposite effects and their antagonism leads to antidepressant effects. This is regulated according to the level of adenosine administered, and at a higher level, the more chances of achieving a positive effect in the treatment (Gomes et al. 2021). Different researches carried out on the genetic encodings of the A1R receptor still have divergences in their conclusions about the effects of the receptor, although there is no evidence about its effective functioning in the brain of humans with MDD. Research involving depressive disorder is induced in rats by different stressful situations, thus, there are different reports on the actions of the receptor. Although some studies demonstrate that stress decreases A1R levels in the hippocampus, others show an increase in the levels of A1R-binding protein in the hippocampus (Gomes et al. 2021).

Thus, even without obtaining a definitive answer about the action of the variation in A1R levels, agonists, antagonists and the deletion on the receptor were studied. A1R agonists potentiate antidepressant effects, reducing behavioral stress situations in rats, both in doses with zinc and in weekly doses. However, the action of an antagonist on the receptor does not demonstrate antidepressant behavioral effects, only blocking adenosine's antidepressant effects. A1R deletion increased the effects of behavioral stress, while overexpression deleted these behaviors and stimulated antidepressant habits. However, there are studies that demonstrate that the effects of this overexpression can vary in different places in the brain (Gomes et al. 2021).

However, higher levels of A2AR demonstrate states of stress and depressive behavior in research with rats. However, other research demonstrates that the ADORA2A gene responsible for encoding the receptor is related to greater resilience to depression, and improvement in common depression behaviors. Other research concludes that there is no correlation between the gene and depressive disorder. Furthermore, there are researches that by genetically overexpressing the A2AR receptor in human neurons, they confirm phenotypes similar to depression (Gomes et al. 2021).

There is significant scientific evidence supporting the action of A2AR antagonists on positive outcomes for common depression phenotypes, while decreasing dopaminergic depolarization. This ability may be related to the concomitant action of other receptor antagonists (such as KW6002 or SCH58261), which together reduced the oxidative stress in the hippocampus, according to postpartum TDM data. In other researches, the use of A2AR antagonists demonstrate resilience to synaptic plasticity and oxidative stress (Gomes et al. 2021).

As in depression, symptoms added to COVID-19 result in greater release of ATP/ADP, stimulating the purinergic system and the actions already described. Thus, the purinergic system and the activation of purinergic receptors can aggravate some neurodegenerative, thrombolytic and platelet symptoms when associated with COVID-19. The formulation of thromboinflammation, in addition to being regulated by thrombin (PAR) signaling and platelet activation, can also be stimulated according to activation of purinergic receptors. From the increase in ATP/ADP, platelet activation causes thrombin to activate fibrinogen, generating fibrin and aggravating conditions willing to formulate thrombi and pro-inflammatory factors. While pulmonary inflammation also releases greater amounts of adenosine and ATP, patients with COVID-19 are more likely to develop thrombosis upon purinergic activation. P2Y1 and P2Y2 receptors were studied for the production of nitric oxide (antithrombotic factor), decreased tissue permeability, and oxidative stress from their inhibitions. Like other adrenergic receptors/ATP, P2Y6 is involved in lung injuries, as well as influences inflammatory conditions as well as P2X7 (Sriram and Insel 2021).

Currently, several studies are studying the potential of antagonism or deletion of the P2X7 receptor as a possible option for reducing the symptoms of COVID-19. There is evidence of its role in inflammatory diseases, sepsis, acute/chronic infections, lung and brain inflammation, in which the receptor ends up stimulating and aggravating these factors because it is linked to inflammation pathways (Ribeiro et al. 2019). Thus, since these symptoms are evidenced in patients with COVID-19, as well as mediated by the same inflammatory pathway in depression, purinergic control as a treatment for such pathologies can be a positive hypothesis to avoid psychiatric disorders and inflammatory diseases, such as SARS-CoV-2 infection (Fig. 3).

Outline of the proposal of the P2X7 receptor as a modulator of the consequences of the cytokine cascade. Proposed therapeutic scheme to stabilize the consequences of increased ATP/Ado when evidenced by oxidative stress and cytokine storm. As Ado receptors involved in depression and neuroinflammation, A1R and A2AR are responsible for controlling synaptic plasticity and releasing several neurotransmitters, including a decrease in available serotonin. Furthermore, the A2AR receptor is also related to suicide attempts precisely because of its potential for neuroplasticity and neuroinflammation. As the ATP receptor involved in depression and neuroinflammation, there is P2X7, which can increase the concentration of pro-inflammatory cytokines (IL-1β and TNF-α), and consequently lead to the development of depressive disorder and COVID-19 morbidities. As a therapeutic potential, there is the P2X7 antagonist, which by blocking this receptor, reduces the cytokine storm, increases 5HT and BDNF, reducing depressive phenotypes, which may reduce depression