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A depressão é um distúrbio multifatorial e de alta prevalência, com sérias consequências ao indivíduo deprimido e à sociedade. Os estudos acerca da neurobiologia da depressão objetivam a busca de novos fármacos antidepressivos e o entendimento das bases neurais e mecanismos celulares e moleculares subjacentes à patologia. Nesse sentido, a interação entre os receptores P2X7 e inflamassoma NLRP3 parecem modular as consequências comportamentais da exposição ao estresse e a resposta a fármacos antidepressivos. Dessa maneira, o presente trabalho teve como hipótese que o tratamento com antagonista purinérgico seria capaz de prevenir o desenvolvimento de comportamentos tipo-depressivos e que essa prevenção envolveria o controle da ativação da cascata NLRP3/caspase-1/IL-1β. De maneira complementar, hipotetizamos também que o tratamento com o inibidor da cascata de inflamassoma NLRP3 seria capaz de prevenir os efeitos comportamentais induzidos pelo estresse e que este efeito teria o envolvimento de componentes do sistema purinérgico. Os resultados mostraram que o tratamento repetido com fluoxetina (10mg/kg) foi capaz de induzir efeito tipoantidepressivo em parte dos animais submetidos ao modelo de desamparo aprendido, sendo os níveis de RNAm de NLRP3 no HPCd destes animais menores do que os animais não responsivos ao tratamento, indicando que a supressão da via P2X7-NLRP3 pode fazer parte do mecanismo de ação da fluoxetina. O tratamento com BBG (antagonista P2X7), o tratamento com MCC950 (inibidor de inflamassoma) e o tratamento com cetamina não foram capazes de reduzir o número de falhas nos animais submetidos ao modelo de desamparo aprendido. De maneira semelhante, a associação de BBG com fluoxetina e de cetamina com fluoxetina também não apresentou efeito tipoantidepressivo nos animais. A associação de fluoxetina com inibidor de inflamassoma MCC950 foi capaz de reduzir o número de falhas dos animais submetidos ao desamparo aprendido, constituindo uma estratégia farmacológica interessante para reverter as consequências comportamentais do estresse. Depression is a multifactorial and highly prevalent disorder, with serious consequences for depressed individuals and society. Studies on the neurobiology of depression aim to search for new antidepressant drugs and to understand the neural bases and cellular and molecular mechanisms underlying the pathology. In this sense, the interaction between P2X7 receptors and NLRP3 inflammasome seems to modulate the behavioral consequences of stress exposure and the response to antidepressant drugs. Thus, the present study hypothesized that treatment with a purinergic antagonist would be able to prevent the development of depressive-like behaviors and that this prevention would involve controlling the activation of the NLRP3/caspase-1/IL-1β cascade. In a complementary way, we also hypothesized that treatment with the NLRP3 inflammasome cascade inhibitor would be able to prevent the behavioral effects induced by stress and that this effect would involve components of the purinergic system. The results showed that the repeated treatment with fluoxetine (10mg/kg) was able to induce an antidepressant-like effect in part of the animals submitted to the learned helplessness model, with the levels of NLRP3 mRNA in the HPCd of these animals being lower than in the non-responsive animals, indicating that suppression of the P2X7- NLRP3 pathway may be part of fluoxetine\'s mechanism of action. Treatment with BBG (P2X7 antagonist), treatment with MCC950 (inflammasome inhibitor), and treatment with ketamine was not able to reduce the number of failures in animals subjected to the learned helplessness model. Similarly, the association of BBG with fluoxetine and ketamine with fluoxetine also did not show an antidepressant-like effect in the animals. The association of fluoxetine with MCC950 (inflammasome inhibitor) was able to reduce the number of failures in animals subjected to learned helplessness, being an interesting pharmacological strategy to reverse the behavioral consequences of stress.

Studies about the pathogenesis of mood disorders have consistently shownthat multiple factors, including genetic and environmental, play a crucial roleon their development and neurobiology. Multiple pathological theories havebeen proposed, of which several ultimately affects or is a consequence ofdysfunction in brain neuroplasticity and homeostatic mechanisms. However,current clinical available pharmacological intervention, which is predominantlymonoamine-based, suffers from partial and lacking response even after weeks ofcontinuous treatment. These issues raise the need for better understanding ofaetiologies and brain abnormalities in depression, as well as developing noveltreatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO system in depression, highlighting potential targets which may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.

Animal studies have shown that antagonists of receptor 1 of Melanin-Concentrating Hormone (MCH-R1) elicit antidepressive-like behavior, suggesting that MCH-R1 might be a novel target for the treatment of depression and supports the hypothesis that MCHergic signaling regulates depressive-like behaviors. Consistent with the evidence that MCHergic neurons send projections to dorsal and median raphe nuclei, we have previously demonstrated that MCH microinjections in both nuclei induced a depressive-like behavior. Even though MCH neurons also project to Locus coeruleus (LC), only a few studies have reported the behavioral and neurochemical effect of MCH into the LC. We studied the effects of MCH (100 and 200 ng) into the LC on coping-stress related behaviors associated with depression, using two different behavioral tests: the forced swimming test (FST) and the learned helplessness (LH). To characterize the functional interaction between MCH and the noradrenergic LC system, we also evaluated the neurochemical effects of MCH (100 ng) on the extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC), an important LC terminal region involved in emotional processing. MCH administration into the LC elicited a depressive-like behavior evidenced in both paradigms. Interestingly, in the LH, MCH (100) elicited a significant increase in escape failures only in stressed animals. A significant decrease in prefrontal levels of NA was observed after MCH microinjection into the LC. Our results demonstrate that increased MCH signaling into the LC triggers depressive-like behaviors, especially in stressed animals. These data further corroborate the important role of MCH in the neurobiology of depression. Agencia Nacional de Investigación e Innovación Programa de Desarrollo de las Ciencias Básicas

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.