| Part I Effects of chronic unpredicted mild stress and different antidepressants treatment on the behavior of SD ratsBackground:Depression is considered to be the most common mental disorder, with complicated pathogenesis and various inducement factors. Besides, the obscure invasion, long disease duration and high recurrence rate become the characteristics of clinical depression. Up to date, the classic tricyclic antidepressant, selective serotonin reuptake inhibitors and some other antidepressants improve the therapeutic safety and tolerance, but the slow onset and long time to fully activation comprise its major disadvantage. TREK-1(TWIK-related K+ channel 1) potassium channel is one of the members of the family of two pore domain potassium channels, makes up of four transmembrane segments and two pore-forming domains. Recent studies have found that TREK-1 potassium channel play an important role in the process of depression therapy. Knockout or block of TREK-1 potassium channel in mice display dramatically early antidepressant effect, however, whether antagonism of TREK-1 potassium channel in adult Sprague Dawley (SD) rats also has an early anti-depressive behavior influence is unclear.Objective:To investigate the onset time of different antidepressants on the behavior of depressed rats by comparing traditional antidepressant and newly TREK-1 potassium channel blockades. Base on the existing results, we hope to provide certain theoretical support for the development of new clinical rapid antidepressant drugs.Methods:Isolated raised rats were exposed to chronic unpredicted mild stress for 56 days, and at the middle of this duration, certain behavior tests (sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT)) were employed to assess the performance of all experimental rats. The depressed rats were treated with drug in the following study, while the rest unsuccessfully depressive rats were continue to receive unpredicted mild stress. The depressed rats were divided into four subgroups, with the treatment of saline, fluoxetine, spadin and SID1900 respectively for the next 28 days, meanwhile, the normal group was also organized into 4 matched subgroups. Behavior performance and change of body weight of all experimental rats were observed after treatment with drug for 7,14,21 and 28 days.Results:Compared to the control group, the body weight, sucrose consumption ratio in sucrose preference test (SPT) and total distance and rearing times in open field test (OFT) (all P<0.001) decreased significantly, while the time of immobility in forced swimming test (FST) (P<0.001) increased dramatically in depressed rats after the model stimulation. After treatment with antidepressants for 7 days, the sucrose preference percentage (P<0.001) of group CUMS+SPA increased significantly and the immobile time (P<0.05) shortened obviously compared with group CUMS, meanwhile, there was no significant difference on the behavior traits of group CUMS+FLU and group CUMS+SID (all P>0.05) compared with group CUMS. Drug intervention for 14 days, compared to group CUMS, the sucrose consumption ratio in SPT and total distance and rearing times in OFT of both group CUMS+SPA and group CUMS+SID increased dramatically and the immobile time reduced markedly (all P<0.05), yet the behavior performance of group CUMS+FLU still showed no significant difference. Notablely, the behavioral performance of group CUMS+SID and group CUMS+SPA in FST and OFT (all P<0.05) improved observably in comparison with group CUMS+FLU. After the drug treatment for 21 days, the rats’presentation of group CUMS+SPA and group CUMS+SID in all three behavior tests displayed significant difference compared with group CUMS, at the same time, the sucrose preference percentage and locomotor capacity of group CUMS+FLU demonstrated an increasing tendency as well as the shorter immobility in FST (P>0.05). After treatment with antidepressants for 28 days, the sucrose consumption ratio and the total locomotor activity of depressed rats with antidepressants treatment (P<0.01) increased significantly compare to group CUMS, and the time of immobility in FST reduced sharply (P< 0.001). Besides, compared with group CUMS, the body weight of group CUMS+SID increased distinctly at the time of treatment with drug for 7 days, and the longer drug delivery, the effect more obvious. Only at the end of the experimental period, the average weight of group CUMS+FLU exerts remarkable recovery (P <0.05). The body weight of group CUMS+SID is larger than which in group CUMS+FLU since the day of 14 after medicine administration, and there exists significant difference (P< 0.05). On the contrary, antidepressant treatment had no valid effects on the behavioral performance and body weight of normal SD rats at different time points (P>0.05).Conclusion:The depressive behavior of CUMS rats can be reversed dramatically by antidepressants, furthermore, the antidepressant effect of TREK-1 potassium channel blockade appears earlier than the classical antidepressants fluoxetine.Background:The hippocampus has long been associated with learning and memory processes, but there is increasing evidence shows that this structure is also involved in the modulation of chronic stress and emotional responses as well as the negative feedback regulation of the hypothalamus-pituitary-adrenal axis. Brain imaging studies have revealed atrophy or loss of neurons in hippocampus of depressed patients, which results in decreased local information transfer and reduced neurogenesis. However, this alteration in hippocampus of depressed person may be reversed by chronic antidepressants treatment.Objective:To explore the changes of nerve regeneration in Dentate Gyrus (DG) region of rats after treatment with different antidepressants in order to provide basic experimental supports for the mechanisms of depression in the aspects of neurogenesis.Methods:Isolated raising and chronic unpredicted mild stress were employed to adult healthy SD rats for 56 days, and at the middle of this duration, behavior tests were used to assess the performance of all experimental rats. The depressed rats were treated with drug in the following 28 days, while the rest unsuccessfully depressive rats were exposed to stress continuously. The depressed rats were divided into four subgroups, with the treatment of saline, fluoxetine, spadin and SID 1900 respectively. Similarly, the normal group was also organized into 4 matched subgroups. Cell proliferation (BrdU+cells) in the main neurogenic zones of hippocampus was analyzed by immunohistochemistry technique, the differentiation (NeuN+/BrdU+cells and GFAP+/BrdU+cells) of new born cells in DG area was revealed by double immunofluorescence method and the apoptosis within new neurons (TUNEL/BrdU+ cells) was tested by double immunofluorescence technique.Results:The chronic antidepressant treatment would promote the proliferation of new cells in DG area of normal rats especially for the subgroup of spadin administration (P<0.05), but antidepressant treatment had no effects on the differentiation and apoptosis within newborn cells for normal rats. Compared with normal rats, the number of new born cells in DG area was reduced significantly by the stimulation of chronic stress (P<0.01). Besides, the percentage of newborn hippocampus cells towards glia in group CUMS increased obviously (P<0.05) and the ratio of differentiation in the direction of neuron reduced significantly in comparison with group CON (P< 0.001). In addition, the apoptosis within newborn cells increased significantly after long exposure to stress (P< 0.001). But on the contrary, drug administration reversed this reduction of proliferation induced by chronic stress in DG area considerably (P< 0.001). Furthermore, compared with the proportion of neuron cells in all newborns of hippocampus in group CUMS, the percentage of group CUMS+FLU, group CUMS+SPA and group CUMS+SID was observed to be increased significantly in DG region (P<0.01, P<0.001, P<0.001 respectively), and the percentage of glia was decreased markedly (P<0.05, P<0.01, P<0.05 respectively). Interestingly, the ratio of apoptosis among all newborns in group CUMS+SPA and group CUMS+SID decreased significantly in comparison with group CUMS (P<0.01).Conclusion:The decreased neurogenesis in DG region of hippocampus induced by chronic unpredicted mild stress is dramatically reversed by antidepressants, and the ability of promoting regeneration of TREK-1 potassium channel blockers is higher than the classical antidepressant fluoxetine. |
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