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Molecular mechanisms involved in the behavioral phenotype of iNOS Knockout animals exposed to a test predictive of antidepressant-like effects


Several studies indicate that inhibition of nitric oxide (NO) induces antidepressant-like effects in animal models. Recent evidence from our research group suggest that the inducible isoform of NO synthase (iNOS) plays an important role in regulating the production of NO during exposure to stress, since its pharmacological inhibition or its gene expression (knockout, KO) induces antidepressant-like effect in the forced swimming test. However, the molecular mechanisms involved in these effects remain unknown. Preliminary evidence indicates that iNOS-KO animals have high levels of nitric oxide (NO) in the prefrontal cortex (PFC), due to a compensatory increase in activity of neuronal nitric oxide synthase (nNOS), but normal or reduced (in response to stress) for NOx and nNOS in the hippocampus (HPC). Thus, these animals are an important experimental tool to investigate the involvement of iNOS in the neurobiology of depression, as well as the changes caused by excessive production of NO in the CPF, especially those related to compensatory homeostatic responses that protect the brain in pathological situations where there excessive NO production. Thus, it becomes important to study the molecular mechanisms involved in these effects. Considering the close relationship between glutamatergic and nitrergic systems in the CNS, we intend to investigate the expression of glutamate receptors (AMPA and NMDA) and nNOS and molecules known to be involved in depression neurobiology (BDNF and its receptor, TrkB, and mTOR ), both in the hippocampus and in CPF animals of WT and iNOS-KO. Moreover, seeking to establish a causal relationship between these factors, we intend to evaluate how pharmacological blockade of AMPA receptors, TrkB or mTOR could affect the behavior of iNOS-KO animals submitted to forced swim test. (AU)

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