Dose-related Effects Of Venlafaxine On PCREB And BDNF In The Hippocampus And Medial Prefrontal Cortex Of The Rat By Chronic Unpredictable Mild Stress

ObjectsStudies in humans and animals have demonstrated that sress and depression are associated with neuronal atrophy and dendritic reorganization in the hippocampus and prefrontal cortex.The aim of the present study was to take advantage of proteins CREB and BDNF which are dynamically regulated in response to different kinds of neuronal plasticity and to examine changes in their mRNA and protein levels in the hippocampus and medial prefrontal cortex of rats by chronic unpredictable mild stress treated chronically with the antidepressant, venlafaxine.To explore the effects of CREB and BDNF on the mechanisms underlying antidepressant action.MethodsSprague-Dawley rats were exposed to a variety of chronic unpredictable mild stressors to create a depression model.Ten rats in each treatment group,were used in all experiment.Rats were treated either 14 days or 28 days with venlafaxine(5 and 10mg/kg,respectively)and the levels of cyclic-AMP response element binding protein(CREB)and brain-derived neurotrophic factor(BDNF)mRNA and protein were assessed using enzyme-linked immunoassay(ELISA),Immunohistochemistry,Western Blot and reverse transcription polymerase chain reaction(RT-PCR).Results1.CUMS rats significantly reduced the consumption of sucrose intake and gained body weight more slowly,compared to control rats; CUMS rats also exhibited a decrease in open field behavior.The rat model of depression has been established successfully at 28th day.2.Low and high doses of venlafaxine(5 and 10mg/kg)increased serum BDNF levels in CUMS rats.3.The present results demonstrated that exposure of CUMS 28 days later downregulated(p)CREB,BDNF mRNA and protein in the hippocampus of CUMS rats,compared to control rats.Initial mapping revealed that low dose of venlafaxine(5mg/kg)treatment increased expression of two plasticity-associated proteins in the hippocampus, compared to CUMS rats.High dose of venlafaxine(10mg/kg),however, decreased expression of two plasticity-associated proteins in the hippocampus,compared to CUMS rats.4.The present results demonstrated that exposure of CUMS 28 days later downregulated CREB,BDNF mRNA in the medial prefrontal cortex of CUMS rats,compared to control rats.Chronic administration of venlafaxine(5mg/kg),to CUMS rats resulted in a significant increase in mRNA of CREB and BDNF in the medial prefrontal cortex.High dose of venlafaxine(10mg/kg),however,decreased in mRNA of CREB and BDNF in the medial prefrontal cortex,compared to CUMS rats.pCREB immunoreactivity were changed most prominently in layersâ…¡-â…¢and â…£-â…¤of the medial prefrontal cortex.Low and high doses of venlafaxine (5 and 10mg/kg)did not change BDNF levels in the medial prefrontal cortex of CUMS rats.ConclusionThe effects of antidepressant on plasticity-associated proteins were associated with the dose of venlafaxine.Our findings suggest that neuronal plasticity-associated proteins such as CREB and BDNF play a important role both in stress and in the treatment of depression.