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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.