DISCUSSION AND CONCLUSION
Stress has been recognized as an important factor involved in the development of depression;[14] the rat CMS model, an ethologically relevant animal model of depression, has been used widely to study behaviors associated with depression, mechanisms of antidepressant actions and several biochemical changes.[232425] The open-field test has been used widely to assess emotionality and locomotor performance.[2026] Furthermore, the use of sucrose consumption is valid in relation to the two core symptoms of major depression, i.e., anhedonia and depressed mood.[2126] In this study, depression-like model states were prepared in rats subjected to a combination of housing singly and a series of daily CMS analogs to “stressful life-styles and events” implicated in the etiology of depression.[2728] After 14 days of exposure to chronic stress from which they cannot escape, the stressed rats exhibited behavioral deficits including decreased body weight gain, decreased locomotor activity in open-field and reduction in sucrose consumption. At the same time, the present study indicated that CHSGS or fluoxetine reversed almost all behavioral alterations observed in the model. Our results are in concordance with data from other studies, which demonstrate that chronic CHSGS treatment reverses chronic mild stress (CMS) - induced behavioral disorders and confirmed previous studies.[101112] It thus appears that there is significant efficacy for CHSGS in treatment of depression.
The neuronal mechanisms that turn stress signals into behavioral disorders are far from understood. Studies thus far, however, have suggested that the mitogen-activated protein kinase (MAPK) signaling transduction pathways contribute to various stress-induced synaptic plasticity and may be the mechanism of antidepressant action and the pathophysiology of depression.[2930] ERK1/2 is the most studied members of MAPK family and the ERK1/2 pathway is the major convergence point in all signal pathways, When activated, the phosphorylation state of ERK1/2, P-ERK1/2 can translocate into nucleus carrying extracellular stimuli primarily regulating cellular growth and differentiation and neuronal plasticity.[31] ERK1 and ERK2 are prominently found in the hippocampus, which is one of the brain regions most likely to be implicate stress response and depression.[3233] In the recent studies, researchers have indicated that ERK1/2 signal transduction pathway may be not only related to stress-induced behavior disorders but involved in the molecular mechanism of antidepressant action.[1530] The signal conduction molecule, ERK1/2, plays an important role in stress-induced activity of neurons in brain; and P-ERK1/2, its active form, has been used as a new marker for the activity of neurons in functional morphology study.[153031] It was found in this research that, after the inducing of chronic stress, levels of P-ERK1/2 in model rats’ hippocampus evidently reduced, especially P-ERK1; And the ratio of the P-ERK1/2 to total ERK1/2 was also decreased in the hippocampus. However, no statistical difference between the rats exposed to 28-day-CMS and the normal group was observed in ERK1/2 levels in the hippocampus. CHSGS or fluoxetine reversed the stress-induced disruption of P-ERK1/2 and increased the ratio of the P-ERK1/2 to total ERK1/2, which is indicated by the increased levels of P-ERK1/2 and the increased ratio of the P-ERK1/2 to total ERK1/2 in the hippocampus in CHSGS group and fluoxetine group compared with model group. Our results are in accordance with previous reports, which indicate decreased P-ERK1/2 in depressed human beings and in depressed rats.[3435] Although recent documents indicate that lithium, valproate, fluoxetine and fluvoxamine, some medications largely used for the treatment of bipolar disorder illness can exert mood-elevating effect through activating the ERK pathway;[173637] the effect exerted by CHSGS on the ERK signal system in brain has not been documented and the present study demonstrated for the first time that CHSGS reversed the stress-induced decrease of the P-ERK1/2 levels and increased the ratio of P-ERK1/2 to total ERK1/2 in the hippocampus and the statistical analysis showed that the effect of CHSGS was similar to fluoxetine.
In conclusion, the present study demonstrated that CMS decreased P-ERK1/2 levels and the ratio of P-ERK1/2 to total ERK1/2 in the hippocampus and induced depressive-like behaviors and CHSGS alleviated the depressive-like behaviors and increased levels of P-ERK1/2 and the ratio of P-ERK1/2 to total ERK1/2. Basing on the results, the mechanism that CHSGS exerts antidepressant actions might be mediated by reversing the stress-induced disruption of ERK activity.