RESUMO
The rapid antidepressant effects of ketamine depend on the N-methyl-D-aspartate (NMDA) receptor containing 2B subunit (NR2B), whose function is influenced by its phosphorylated regulation and distribution within and outside synapses. It remains unclear if ketamine's rapid onset of antidepressant effects relies on the dynamic phosphorylated regulation of NR2B within and outside synapses. Here, we show that ketamine rapidlyalleviated depression-like behaviors and normalized abnormal expression of pTyr1472NR2B and striatal-enriched protein tyrosine phosphatase (STEP) 61 within and outside synapses in the medial prefrontal cortex (mPFC) induced by chronic unpredictable stress (CUS) and conditional knockdown of STEP 61, a key phosphatase of NR2B, within 1â¯hour after administration Together, our results delineate the rapid initiation of ketamine's antidepressant effects results from the restoration of NR2B phosphorylation homeostasis within and outside synapses. The dynamic regulation of phosphorylation of NR2B provides a new perspective for developing new antidepressant strategies.
Assuntos
Antidepressivos , Depressão , Ketamina , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Ketamina/farmacologia , Animais , Fosforilação/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/genética , Tirosina/metabolismo , Camundongos , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Comportamento Animal/efeitos dos fármacosRESUMO
The relationship between circadian rhythms and mood disorders has been established. Circadian dysregulations are believed to exacerbate the severity of mood disorders and vice versa. Although many studies on diurnal changes of clock genes in animal model of depression have been performed from the RNA level, only a few studies have been carried out from the protein level. In this study, we investigated the diurnal changes induced by chronic unpredictable stress (CUS) using free-running wheel test and Western Blotting (WB). Besides, we examined the depression-like behaviors of rats by sucrose preference test (SPT) and forced swim test (FST). We found that CUS induced significant reductions in the quantity of free-running wheel activity and rhythmic disruptions of clock proteins in hippocampus. Furthermore, we found that the amplitude of PER1 in CA1 was positively related to the severity of depression-like behaviors. These results suggest that CUS results in both changes in diurnal rhythms and in depression-like behaviors and that it is suggested that these changes are related.
Assuntos
Ritmo Circadiano , Depressão/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal , Região CA1 Hipocampal/metabolismo , Proteínas CLOCK/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Atividade Motora , Proteínas Circadianas Period/metabolismo , Condicionamento Físico Animal/métodos , Ratos , Ratos Sprague-Dawley , Sacarose/metabolismo , NataçãoRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor because of serious doubts regarding the data on melatonin levels. The authors used a melatonin ELISA kit that was not fit for purpose, resulting in data showing peak secretion of this hormone occurring in the middle of the light period, which does not make any physiological sense since melatonin is only produced during darkness.
RESUMO
The relationship between circadian rhythms and mood disorders has been established, circadian dysregulations are believed to exacerbate the severity of mood disorders and vice versa. Although many studies on diurnal changes of clock genes in animal model of depression have been performed from the RNA level, only a few studies have been carried out from the protein level. In this study, we investigated the diurnal changes induced by chronic unpredictable stress (CUS) using various methods, including free-running wheel test, enzyme-linked immunosorbent assay (ELISA) and Western Blotting (WB). Besides, we examined the depression-like behaviors of rats by sucrose preference test (SPT) and forced swim test (FST). We found that CUS induced significant reductions in the quantity of free-running wheel activity and the amplitude of melatonin secretion rhythm. We also found that CUS induced rhythmic disruptions of clock proteins in hippocampus. Furthermore, we found that the amplitude of PER1 in CA1 was positively related to the severity of depression-like behaviors. These results suggest that stress results in both changes in circadian rhythms and in depression-like behaviors and that it is suggested that these changes are related.