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PEREIRA, V.S. Participation of NMDA-NO pathway from the medial préfrontal córtex on the behavioural consequences of forced swim stress: molecular mechanisms. 2015. 191p. Thesis (Doctoral) – School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 2014. The activation of NMDA receptors is capable of increasing nitric oxide (NO) synthesis in the brain. The administration of NMDA antagonists (e.g., ketamine) or nitric oxide synthesis inhibitors (e.g., 7-NI) produce antidepressant-like effects in animals and highlights the potential of glutamatergic and nitrergic systems as therapeutic targets for the treatment of major depression. The involvement of intracellular mechanisms associated to neural plasticity, such as BDNF-TrkBmTOR pathway, has been implicated in the antidepressant-like effects induced by systemic administration of NMDA antagonists. For instance, the antidepressant effects of ketamine are associated with increased BDNF synthesis and mTOR in the medial prefrontal cortex (vMPFC). In addition, injection of an NMDA antagonist (LY235959) into the vMPFC-PL produces antidepressant-like effect in animals. However, it is not yet known if the aforementioned antidepressant-like effects involve the modulation of NO synthesis or the activation of the BDNF-TrkB-mTOR pathway in the vMPFC. Therefore, this work investigated the involvement of glutamatergic and nitrergic neurotransmission of the vMPFC, as well as the participation of local BDNF-TrkBmTOR pathway, in the modulation of behavioral responses of animals submitted to forced swimming test, an animal model predictive of antidepressant effects. The administration of nNOS inhibitor (NPA), sGC inhibitor (ODQ) or NO scavenger (c-PTIO) into the vMPFC-PL produced antidepressant-like effects, similarly to what has been previously described with the local injection of LY235959. The effects of LY235959 were blocked by pretreatment with an antagonist of AMPA receptors (NBQX), but not the NPA effects. Thus suggesting a possible dissociation between NMDAand NO-induced mechanism in the PL. BDNF administration in the PL induced antidepressant-like effect, which was blocked by prior administration of the TrkB receptor antagonist (K252a) or the mTOR inhibitor (rapamycin). The antidepressant-like effects induced by intra-PL administration of LY235959 and NPA, into vMPFC-PL were not altered in the presence of K252a. However, the prior administration of rapamycin was able to block the effects of LY235959, but not NPA-induced effect. This result further supports the dissociation of the NMDA-NO system in the PL in the modulation of immobility in the FST. Systemic treatment with ketamine (NMDA antagonist) or 7-NI (nNOS inhibitor) produced antidepressant-like effects in the FST, although these treatments did not affect the activation or the expression of TrkB receptors or mTOR in the MPFC of stressed animals. These results further corroborate the involvement of the glutamatergic and nitrergic neurotransmission in the modulation of behavioral consequences of the forced swim stress and highlight that the interaction of these systems with mTOR and trkB in the PL is considerably complex. Altogether, our data supports the possible modulation of BDNF-TrkBmTOR pathway of the PL in the effects induced by NMDA antagonist injection.. However, the effects induced by inhibitors of the NO pathway semms dissociated from an interaction with the aforementioned pathway. Thus, further studies are necessary to clarify the interaction of glutamatergic and nitrergic neurotransmission with BDNF-TrkB-mTOR pathway into vMPFC-PL regarding the neurobiology of stress and depression.

Participação da via NMDA-NO do córtex pré-frontal medial ventral na modulação das consequências comportamentais do estresse de nado forçado: mecanismos intracelulares