| 【Objective】 To investigate the relationships between depression andhistone acetylation as well as monoamine neurotransmitter system-andneurotrophin-related genes expression, and to explore the interventioneffect of venlafaxine in a rat depression model induced by chronicallyunpredictable stress.【Method】80male Sprague-Dawley rats (8weeks,180-200g) were usedto screen and then randomly divided into four groups: control group(Control), chronically unpredictable stress group (CUS), venlafaxine group(VLX), and VLX plus CUS group (VLX+CUS). Depression model wasestablished by CUS with solitary life. At the same time, velafaxine(23.4mg/kg once daily) or the same volume of vehicle was administered toexperimental rats by intragastric gavage according to the requirements ofdivided groups. Depressive behavior was evaluated by open field test(OFT), forced swim test (FST) and sucrose preference test; corticosterone(CORT) level in the serum was determined by radioimmunoassay;hippocampal pathomorphology was determined with HE staining； malondialdehyde (MDA) level, superoxide dismutase (SOD) and catalase(CAT) activity in the serum, cortex and hippocampus were analyzed bybiochemical method； real-time PCR was applied to detect mRNAexpression of CRF in the hypothalamus, TH and TPH in the cortex andhippocampus, and IDO, MAO-A, BDNF and GSK-3β in the hippocampus;western blot was used to test the protein expression of CRF in thehypothalamus, TH and TPH in the cortex and hippocampus, and aH3(K9),aH3(K14), aH4(K12), HDAC5in the hippocampus.【Result】1. At the4th week of the experiment, compared with control rats, themodel rats had significantly decreased ambulation and rearing score inthe OFT and obviously prolonged immobility time in FST. Venlafaxineadministration obviously inhibited the behavioral changes above causedby CUS. However, venlafaxine failed to show significant influences onbehaviors of control rats.2. Compared with control rats, the model rats showed a significantlyhigher serum CORT level with a markedly increased CRF expression inthe hypothalamus; and they also presented obviously higher MDAlevels in the serum, cortex, and hippocampus with decreased SOD andCAT activity. Venlafaxine remarkably decreased the CRF expressionand promoted the antioxidant ability of CUS rats except that of controlrats. 3. Compared with control rats, the hippocampal CA2and CA3cells ofmodel rats showed a smaller body volume with obvious pyknosis andkaryorrhexis of hippocampal dentate gyrus cells. Venlafaxine lightenedthe CUS-induced hippocampal neuronal damage and had no obviousinfluences on control rats.4. Compared with control rats, hippocampal aH3(K9) and aH4(K12)expression was significantly decreased in the model rats with anupregulation of HDAC5level.Venlafaxine clearly blunted CUS-induceddecrease of aH3(K9) and aH4(K12) and increase of HDAC5expression without significant influences on that from control rats.5. Compared with control rats, there existed clearly decreased expressionof both TH, TPH mRNA and protein in the cortex and hippocampus ofmodel rats with markedly reduced BDNF mRNA expression andincreased IDO, MAO-A, and GSK-3β mRNA expression in thehippocampus. Venlafaxine significantly increased the TH, TPH, BDNFexpression and reduced the MAO-A expression in the CUS rats. It hadno obvious influences on that of control rats.【Conclusion】1. CUS make the rats display obvious depression-and despair-likebehavior and resulted in pathomorphological changes of hippocampalneurocytes.2. The mechanisms of CUS-induced rat depression may be associated with inducing HPA axis dysfunction, oxidative stress, histone hypoacetylati-on, and subsequent monoamine neurotransmitter and neurotrophydeficiency caused by epigenetic regulation.3. The antidepressant effect of venlafaxine may be associated withimproving HPA axis function, reversing the oxidative stress andanti-oxidative stress imbalance, elevating histone acetylation andsubsequently increasing monoamine neurotransmitter and neurotrophin. |
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