Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN

The renin-angiotensin system (RAS) is associated with peripheral fluid homeostasis and cardiovascular function, but recent evidence also suggests a functional role in the brain. RAS regulates physiological and behavioral parameters related to the stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain-derived neurotrophic factor (BDNF) and TRKB, which are important in the neurobiology of depression and antidepressant action. However, the interaction between the BDNF/TRKB system and RAS in depression has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treatment. Moreover, infusion of losartan into the ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked the consequences of systemically injected losartan, whereas K252a (a blocker of TRK) infused into these brain areas impaired such effect. PD123319, an antagonist of AT2 receptor (AGTR2), also prevented the systemic losartan effect when infused into PL but not into vHC. Cultured cortical cells of rat embryos revealed that angiotensin II (ANG2), possibly through AGTR2, increased the surface levels of TRKB and its coupling to FYN, a SRC family kinase. Higher Agtr2 levels in cortical cells were reduced after stimulation with glutamate, and only under this condition an interaction between losartan and ANG2 was achieved. TRKB/AGTR2 heterodimers were also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, the antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 towards AGTR2, followed by coupling of TRK/FYN and putative TRIG transactivation. Thus, the blockade of AGTR1 has therapeutic potential as a novel antidepressant therapy. (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Involvement of the NMDA-NO pathway of the dorso/ventral hippocampal axis in the modulation of behavioral responses elicited by the forced swimming test

Acredita-se que diferenças hodológicas e diferente padrão de expressão gênica ao longo do eixo dorso/ventral do hipocampo seriam responsáveis pela distinta função entre a porção dorsal (HD) e ventral do mesmo (HV). HD seria responsável por processos cognitivos, tais como memória e aprendizagem espacial, e o HV pelas respostas neuroendócrinas e emocional-motivacionais ao estresse. No entanto, não há muitos estudos acerca de diferenças entre HD e HV na modulação de comportamentos relacionados à neurobiologia da depressão. Há, contudo, dados indicando que o bloqueio de receptores glutamatérgicos do tipo NMDA ou da síntese de NO no HD induz efeito semelhante ao dos antidepressivos (i.e. do tipo antidepressivo) no teste do nado forçado (TNF). Quanto ao HV, a função da neurotransmissão glutamatérgica/nitrérgica na neurobiologia da depressão permanece não investigado. Dessa forma, o objetivo do presente estudo foi realizar o bloqueio reversível do HD ou do HV, em diferentes momentos, em animais submetidos ao TNF. O próximo passo foi realizar a micro-injeção intra-HD ou intraHV do antagonista NMDA AP-7 ou do inibidor da óxido nítrico sintase neuronal (nNOS), N-PLA, ou do inibidor da guanilato ciclase solúvel (sGC), ODQ. Os resultados mostram que o bloqueio do HD ou do HV com cloreto de cobalto (CoCl2, bloqueador da neurotransmissão sináptica dependente de cálcio) não modificou o comportamento dos animais no TNF. No entanto a administração de AP-7 ou N-PLA ou ODQ no HV antes do teste, reduziu o tempo de imobilidade no TNF. Por outro lado, a injeção dessas drogas no HD foi capaz de reduzir o tempo de imobilidade quando administradas tanto depois do pré-teste quanto antes do teste. Estes resultados sugerem que as vias NMDA-NO do HD e do HV, estariam envolvidas na modulação da resposta comportamental frente ao estresse do nado forçado. Além disso, os dados indicam que a participação dessas estruturas é importante em diferentes momentos após a exposição ao estresse.It is believed that hodological and genetic pattern of expression differences along dorsal/ventral hippocampal axis would be responsible for distinct functions attributed to its dorsal (DH) and ventral (VH) poles. DH would be responsible for cognitive process, such as spatial memory and learning, whereas the VH would be responsible for neuroendocrine and emotional-motivation responses to stress. However, there is no many studies about possible differences between DH and VH in the modulation of behavioral responses related to the neurobiology of depression. Though, there are data showing that the blockade of glutamatergic NMDA receptors blockers or NO synthesis inhibition within the DH induces similar effect to that of antidepressant drugs (like antidepressant effect) in the forced swimming test (FST). On the VH, The role of the glutamatergic/nitrergic neurotransmission remains to be investigated. Thus, the aim of this work was to perform the reversible blockade of DH or VH, at different times, in animals subjected to FST. Additionally, the next step was to perform a microinjections into the DH or the VH of NMDA antagonist (AP-7), inhibitor of neuronal nitric oxide synthase (nNOS, N-PLA), or the inhibitor of soluble guanylate cyclase (sGC, ODQ). The results show that blocking the VH or the DH (cobalt chloride, calcium dependent neurotransmission inhibitor) did not modify the behavior of animals during the TNF. However administration of AP-7, N-PLA or ODQ intra-HV, before testing, caused antidepressant-like effects. Moreover, injection of such drugs, intra-HD, was able to induce similar results when administered both after the pre-test and before testing. These results suggest that NMDA-NO pathway of both VH and DH is involved in the modulation of emotional responses to the forced swim stress, although there may be an interest differential participation of these structures at different times after exposure to stress

Involvement of the NMDA-NO pathway of the dorso/ventral hippocampal axis in the modulation of behavioral responses elicited by the forced swimming test

Acredita-se que diferenças hodológicas e diferente padrão de expressão gênica ao longo do eixo dorso/ventral do hipocampo seriam responsáveis pela distinta função entre a porção dorsal (HD) e ventral do mesmo (HV). HD seria responsável por processos cognitivos, tais como memória e aprendizagem espacial, e o HV pelas respostas neuroendócrinas e emocional-motivacionais ao estresse. No entanto, não há muitos estudos acerca de diferenças entre HD e HV na modulação de comportamentos relacionados à neurobiologia da depressão. Há, contudo, dados indicando que o bloqueio de receptores glutamatérgicos do tipo NMDA ou da síntese de NO no HD induz efeito semelhante ao dos antidepressivos (i.e. do tipo antidepressivo) no teste do nado forçado (TNF). Quanto ao HV, a função da neurotransmissão glutamatérgica/nitrérgica na neurobiologia da depressão permanece não investigado. Dessa forma, o objetivo do presente estudo foi realizar o bloqueio reversível do HD ou do HV, em diferentes momentos, em animais submetidos ao TNF. O próximo passo foi realizar a micro-injeção intra-HD ou intraHV do antagonista NMDA AP-7 ou do inibidor da óxido nítrico sintase neuronal (nNOS), N-PLA, ou do inibidor da guanilato ciclase solúvel (sGC), ODQ. Os resultados mostram que o bloqueio do HD ou do HV com cloreto de cobalto (CoCl2, bloqueador da neurotransmissão sináptica dependente de cálcio) não modificou o comportamento dos animais no TNF. No entanto a administração de AP-7 ou N-PLA ou ODQ no HV antes do teste, reduziu o tempo de imobilidade no TNF. Por outro lado, a injeção dessas drogas no HD foi capaz de reduzir o tempo de imobilidade quando administradas tanto depois do pré-teste quanto antes do teste. Estes resultados sugerem que as vias NMDA-NO do HD e do HV, estariam envolvidas na modulação da resposta comportamental frente ao estresse do nado forçado. Além disso, os dados indicam que a participação dessas estruturas é importante em diferentes momentos após a exposição ao estresse.It is believed that hodological and genetic pattern of expression differences along dorsal/ventral hippocampal axis would be responsible for distinct functions attributed to its dorsal (DH) and ventral (VH) poles. DH would be responsible for cognitive process, such as spatial memory and learning, whereas the VH would be responsible for neuroendocrine and emotional-motivation responses to stress. However, there is no many studies about possible differences between DH and VH in the modulation of behavioral responses related to the neurobiology of depression. Though, there are data showing that the blockade of glutamatergic NMDA receptors blockers or NO synthesis inhibition within the DH induces similar effect to that of antidepressant drugs (like antidepressant effect) in the forced swimming test (FST). On the VH, The role of the glutamatergic/nitrergic neurotransmission remains to be investigated. Thus, the aim of this work was to perform the reversible blockade of DH or VH, at different times, in animals subjected to FST. Additionally, the next step was to perform a microinjections into the DH or the VH of NMDA antagonist (AP-7), inhibitor of neuronal nitric oxide synthase (nNOS, N-PLA), or the inhibitor of soluble guanylate cyclase (sGC, ODQ). The results show that blocking the VH or the DH (cobalt chloride, calcium dependent neurotransmission inhibitor) did not modify the behavior of animals during the TNF. However administration of AP-7, N-PLA or ODQ intra-HV, before testing, caused antidepressant-like effects. Moreover, injection of such drugs, intra-HD, was able to induce similar results when administered both after the pre-test and before testing. These results suggest that NMDA-NO pathway of both VH and DH is involved in the modulation of emotional responses to the forced swim stress, although there may be an interest differential participation of these structures at different times after exposure to stress