P2X7 Receptor Signaling in Stress and Depression

Abstract

Stress exposure is considered to be the main environmental cause associated with the development of depression. Due to the limitations of currently available antidepressants, a search for new pharmacological targets for treatment of depression is required. Recent studies suggest that adenosine triphosphate (ATP)-mediated signaling through the P2X7 receptor (P2X7R) might play a prominent role in regulating depression-related pathology, such as synaptic plasticity, neuronal degeneration, as well as changes in cognitive and behavioral functions. P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling. P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate. Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD. Importantly, blockade of P2X7R leads to antidepressant-like effects in different animal models, which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans. This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…Stress exposure is considered to be the main environmental factor instigating mood disorders in humans, and all animal models of MD are based on exposure to inescapable stress (Ribeiro et al, 2019). Psychological and metabolic stress could induce adrenocorticotropic hormone (ACTH) and glucocorticoid secretion in mice, which were reduced in IL-1 knockouts (KOs) or transgenic animals overexpressing brain IL-1ra, a naturally occurring IL-1 antagonist (Goshen et al, 2003;Liu and Quan, 2018).…”

“…It can be derived from the available literature as discussed in our review that P2X7Rs may be promising targets to treat MD and BD (Bhattacharya, 2018;Wei et al, 2018). However, the following three difficulties are major obstacles in developing new P2X7R antagonists for the treatment of mood disorders: (1) a number of P2X7R antagonists act in rodent receptor orthologs but not in human receptor orthologs when investigated under in vitro conditions (Bhattacharya and Biber, 2016); (2) the disease can be modeled by depressive-like states induced by applying acute or chronic inescapable stress to rodents; however, it is most likely that there is no perfect analogy with the human disease (Ribeiro et al, 2019); and (3) P2X7R antagonists have to pass the blood-brain barrier in order to exert effects in the CNS.…”

“…The mood disorder major depression (MD) is characterized by extreme sadness, depressed mood, and loss of interest that persist for at least 2 weeks and interferes with the individual's social functioning (Harvey et al, 2007;Deussing and Arzt, 2018;Wei et al, 2018;Ribeiro et al, 2019). During bipolar disorder (BD), the mood state cycles between high (mania) and low (depression) episodes.…”

Transcutaneous auricular vagal nerve stimulation inhibits P2X7R expression in limbic brain regions and reverses depression-like behavior in Zucker diabetic fatty rats

“…Recent ndings gradually revealed that ATP-mediated signaling via the P2 × 7 receptors plays a crucial role in regulating depressive pathologies, such as alterations in cognitive and behavioral functions, neuronal degeneration, and synaptic plasticity [12]. There is a lot of evidence that P2 × 7R modulates 5hydroxytryptamine, noradrenaline, glutamate, gamma-aminobutyric acid, and nitric oxide release, which are mechanisms consistently related to depression [13][14][15].…”

“…There is a lot of evidence that P2 × 7R modulates 5hydroxytryptamine, noradrenaline, glutamate, gamma-aminobutyric acid, and nitric oxide release, which are mechanisms consistently related to depression [13][14][15]. Also, P2 × 7R is an essential target in facilitating stress adaptation and supporting potential antidepressant effects through its capability to regulate in ammasome activation [12,[16][17][18]. The results acquired from animal models have provided valuable information regarding the role of P2 × 7R in depressive disorders and stress responses.…”