Molecular Psychiatry https://doi.org/10.1038/s41380-018-0088-3 CORRESPONDENCE Purinergic modulation of pathways associated to suicidal behavior Maria Carolina Bittencourt Gonçalves 1 ● Juliana Corrêa-Velloso 2 ● Yahaira Naaldijk 2 ● Arquimedes Cheffer 2 ● Henning Ulrich 2 Received: 5 March 2018 / Accepted: 9 April 2018 © Macmillan Publishers Limited, part of Springer Nature 2018 In our recent review, we discussed the most recent available literature regarding purinergic system and pathophysiology of psychiatric diseases [1]. Although suicide is a topic that we chose not to explore in a first moment, we understand it as a public health issue lacking substantial discussions and conclusions regarding its neurobiological basis, which might include genetic predispositions, molecular and cel- lular triggers, and epigenetic factors. Moreover, it should be mentioned that suicidal behavior can occur independently of psychiatric diseases and could be considered a disorder by itself. Given that, a special topic should be dedicated to suicidal behavior, being a difficult task due to the lack of functional data linking the purinergic system and suicidal behavior. However, we agree with the fact that indirect evidence exists pointing to the involvement of the purinergic system in the neurobiology of suicide when related to psychiatric disorders, such as depression, and to behavioral phenotypes, such as impulsivity/aggressiveness, as discussed in the Letter to the Editor by Bartoli et al. [2]. The authors of this manuscript appreciably filled in a gap by drawing attention to a possible role of purinergic signaling in suicidal beha- viors linked to depression and impulsivity through adeno- sine A 2A receptor activity, although this association should be carefully considered [2]. Here, we make some additional considerations. A large body of evidence indicates that upregulation of the hypothalamic–pituitary–adrenal (HPA) axis and down- regulation of serotonin transmission are implicated in sui- cide and impulsivity/aggressiveness behavior related to suicide (see an extensive review on this issue by Mann [3]). As stated in our previous review [1], A 2A and A 2B receptors agonism enhances suprarenal corticosterone production [4] (Fig. 1A). Additionally, the activation of A 1 receptors decreases serotonin-mediated postsynaptic currents in the prefrontal cortex [5] (Fig. 1A). An increase in interleukin-1β (IL-1β) production induced by P2X7 receptors has also been observed in depressive-like behaviors [6], and a plethora of inflam- mation mediators, such as IL-1β, appear to be involved in the suicidal behavior. For instance, IL-1β levels are aug- mented in the brain and blood of patients, who either died by suicide or attempted it [7, 8]. Injection of IL-1β into the hypothalamus and the midbrain increased aggressive behavior in an animal model [9, 10]. The resulting hypothesis is that P2X7 receptor induces IL-1β production, which is known for triggering aggressive and suicide behavior (Fig. 1A). So far, much evidence for the involvement of glutamate in suicidal behaviors has emerged and been confirmed by gene expression arrays and body fluid analyses. Glutamate is the most important and abundant excitatory neuro- transmitter in the brain. However, failures in the regulation of its levels can lead to excitotoxicity and pathological cell responses [11]. High levels of glutamate are found in the brain of patients suffering from mood disorders, especially bipolar disorder and major depression [12], which can be associated to increased oxidative stress, neuroinflammation, and cell death [11]. Analysis of postmortem brain of suicide victims with or without history of major depression showed significant changes in the expression of genes controlling glutamater- gic and γ-aminobutyric acid (GABA)ergic neurotransmis- sion [13]. N-methyl-D-aspartate (NMDA) glutamatergic receptors appear to be the most important target of interest to understand and to intervene glutamatergic modulation of suicidality. For instance, postmortem receptor-ligand bind- ing analysis of frontal cortex from suicide victims indicated changes in NMDA receptor complexes [14]. Moreover, * Henning Ulrich henning@iq.usp.br 1 Department of Neurology and Neurosciences, Medical School, Federal University of São Paulo, São Paulo, Brazil 2 Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil 1234567890();,: 1234567890();,: