Objective To investigate the effect of venlafaxine on the depression-like behavior, and the expression of CNPase, MBP and Nrg1 Ⅲ-ErbB2 expression in prefrontal cortex（PFC） of cuprizone（CPZ） treated mice. Methods A total of 32 C57BL/6 male mice aged 8-weeks were randomly divided into control group, venlafaxine（Ven） group, model（CPZ） group and CPZ+Ven group. Mice in CPZ and CPZ+Ven groups were fed with diet containing 0.2% CPZ for 5 weeks to establish CPZ model. Ven and CPZ+Ven groups received 20 mg/（kg·d） venlafaxine by gavage for 5 weeks. Control group and CPZ group were gavaged with 200 μl saline every day during the same time period. Open field experiment, sugar-water preference experiment and tail suspension experiment were carried out after 5-week intervention, and then 5 mice in each group were killed immediately. PFC was collected in liquid nitrogen. The protein levels of CNPase and MBP in PFC were detected by Western blot, and the level of Nrg1 Ⅲ-ErbB2 mRNA was detected by RT-PCR. The remaining mice（n=3） were perfused and fixed with 4% PFA,and then the morphological changes of oligodendrocytes were observed by immunofluorescence staining for CNPase. Results The total distance traveled in open field and distance of central movement of CPZ group were shorter than those of the control group [（12.50±4.73） m vs（25.63±5.64） m,（5.92±1.98） % vs（11.78±4.17） %]. The immobility time of suspended tail test was longer than that of the control group [（153.75±26.4） s vs（71.62±20.95） s]. Sugar preference index was lower than that of the control group [（79.16±6.53） % vs（92.67±2.97） %]. The protein expression levels of CNPase and MBP in PFC were lower than those of the control group [（0.56±0.08） vs（0.85±0.13）,（0.37±0.05） vs（1.01±0.08）]. The mRNA levels of Nrg1Ⅲ and ErbB2 were lower than those of the control group [（0.38±0.27） vs（1.06±0.16）,（0.42±0.41） vs（1.01±0.01）]. The differences of all the above were statistically significant（P ＜ 0.05）. The total distance traveled in open field and distance of central movement of CPZ+Ven group were longer than those of the CPZ group [（22.64±6.59） m vs（12.50±4.73） m,（10.6±2.85） % vs（5.92±1.98） %]. The immobility time of suspended tail test was longer than that of the CPZ group [（109.25±35.69） s vs（153.75±26.4） s].Sugar preference index was lower than that of the CPZ group [（91.63±2.98） % vs（79.16±6.53） %]. The protein expression levels of CNPase and MBP in PFC were lower than those of the CPZ group [（0.84±0.09） vs（0.56±0.08）,（0.71±0.13） vs（0.37±0.05）]. The mRNA levels of Nrg1Ⅲ and ErbB2 were lower than those of the CPZ group [（0.70±0.33） vs（0.38±0.27）,（0.80±0.25） vs（0.42±0.41）]. The differences of all the above were statistically significant（P ＜ 0.05）. CNPase immunofluorescence staining showed that there were fewer CNPase oligodendrocytes in the PFC of mice in the CPZ group than in the control group and the CPZ+Ven group.Conclusions Venlafaxine can up-regulate the levels of CNPase and MBP protein and the mRNA levels of Nrg1Ⅲ and ErbB2 in the PFC of CPZ mice,increase the number of oligodendrocytes,and alleviate depressionlike behaviors.

Objective:To investigate the effects of fluoxetine (Flx) on lipidomics of hippocampal tissue in chronic unpredictable stress (CUS) model rats.Methods:A total of 30 Sprague-Dawley rats were randomly divided into Sham group, CUS group and CUS+ Flx group, with 10 rats in each group. Rats in the CUS group and CUS+ Flx group were received one or two random stimuli every day for 28 days, and then they were received intraperitoneal injection of normal saline(1 ml/kg) and fluoxetine(10 mg/kg) respectively once a day for 14 days. Rats in the Sham group were maintained in their home cages for 28 days, and then received intraperitoneal injection of saline (1 ml/kg) once a day for 14 days. The sugar water preference experiment was carried out 24 hours after the last injection, and then the rats were killed to separate the rat hippocampus. The levels of lipid composition in hippocampus were detected by high performance liquid chromatography-mass spectrometry. The relative content of lipid was analyzed by Simca-p 14.1 and LipidSearch software version 4.1. SPSS 19.0 was used for statistical analysis. One-way ANOVA or Kruskal-Wallis test was used for comparison among groups, and Bonferroni test was used for post-hoc test. Pearson correlation or Spearman correlation was used to analyze the correlation between behavioral indexes and lipid molecular level in hippocampus.Results:There was significant difference in sugar preference test among the three groups ( F=12.830, P<0.001). The percentage of sucrose intake of rats in CUS group ((43.57±12.38)%) was significantly lower than those in Sham group ((67.09±11.81)%) and CUS+ Flx group ((62.74±8.58)%) (both P<0.05). Ninety five differential lipid molecules were screened among the three groups by lipidomic analysis, mainly distributed in glycerophospholipids and sphingolipids. Among them, levels of PE (34∶1e)+ H( r=-0.477), PE(18∶1p/20∶1)+ H( r=-0.433), PE(18∶1/18∶1)+ Na( r=-0.603), PE(36∶2p)-H( r=-0.382), PE(16∶0/20∶4)-H( r=-0.464), PE(18∶0/18.2)-H( r=-0.482), PE(16∶0e/22∶6)-H( r=-0.514), PE(18∶1/20∶4)-H( r=-0.511) and CerG1 (d18∶2/24∶0+ O)+ H( r=-0.490) were negatively correlated with sucrose preference rate (all P<0.05), whereas levels of PE (42∶6p)+ Na( r=0.379), PE(34∶0p)-H( r=0.397) and SM (d22∶1/16.0)+ HCOO( r=0.388) were positively correlated with sucrose preference rate (all P<0.05). Conclusion:Flx improves the depressive-like behavior of CUS model rats, which may be related to the regulation of hippocampal glycerophospholipid and sphingolipid metabolism.

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often results in debilitating involuntary movements known as L-DOPA-induced dyskinesia (LID), which is the main obstacle in PD. The abnormal involuntary movements (AIMs) are consistently involved with the activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway. Previous research has also shown that blockade of ERK phosphorylation could reduce the induction of LID. Consequently, inhibitors of MAPK signaling cascade that block the aberrant supersensitive response of direct pathway striatal neurons could provide a novel therapeutic adjunct to L-DOPA in the treatment of PD. Statins, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity, and the subsequent phosphorylation of ERK1/2 (pERK1/2). Simvastatin, a representative of statins, could reduce L-DOPA-induced AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by preventing the L-DOPA/benserazide-induced increase in pERK1/2 levels in our study. The simvastatin-L-DOPA/benserazide-treated 6-OHDA animals displayed less severe rotational behavior and a dramatic reduction in AIM severity than the L-DOPA/benserazide-treated ones. This lower AIM severity was related to a decrease in L-DOPA-induced increase in the following: (1) striatal pERK1/2 and (2) FosB levels. These results suggest that simvastatin could represent a treatment option for managing LID in PD.