Syndromes and Mechanisms of Depression Induced by Second Hit in Mice / 中国实验方剂学杂志

ObjectiveTo explore the syndromes and mechanisms of depression induced by maternal separation （MS） combined with chronic restraint stress （RS） in mice. MethodOn postnatal day 0 （PD0）， the offspring mice were randomized into a blank group （NC） and a modeling group. The mouse model of depression was established by MS+RS for 21 days. After removal of female mice on PD21， the modeled mice were randomized into model， Wenyang， Jieyu， Wenyang Jieyu， and fluoxetine groups， with 15 mice in each group. The sucrose preference， tail suspension， and open field tests were carried out to evaluate the anxiety and depression-like behavior in mice. Enzyme-linked immunosorbent assay was used to measure the adrenocorticotrophic hormone （ACTH） and corticosterone （CORT） levels in mouse plasma. High performance liquid chromatography-electrochemical detector was used to determine the content of monoamine neurotransmitters in the hippocampus. Real-time fluorescence quantitative polymerase chain reaction was employed to determine the mRNA levels of genes in the 5-hydroxytryptamine （5-HT） system， hypothalamic-pituitary-adrenal （HPA） axis， and brain-derived neurotrophic factor （BDNF） signaling pathway in the hippocampus. Immunohistochemistry was employed to determine the expression levels of proteins in the 5-HT system and HPA axis in the hippocampus. The Simple Western system was used to determine the protein levels of BDNF and tyrosine kinase receptor B （TrkB） in the hippocampus. ResultCompared with the NC group， the model group exhibited depression-like behavior， which was significantly relieved by Wenyang Jieyu prescription and fluoxetine. Compared with the NC group， the model group showed elevated levels of CORT and ACTH in the plasma （P<0.01）， which， however， were lowered by Wenyang Jieyu prescription and fluoxetine （P<0.05， P<0.01）. Compared with the NC group， the model group showed inhibited expression of neurotransmitters in the hippocampus （P<0.05， P<0.01）， while Wenyang Jieyu prescription and fluoxetine restored the expression of neurotransmitters （P<0.05， P<0.01）. Compared with NC group， the model group showed inhibition of the 5-HTergic nerve and abnormal activation of the HPA axis， and Wenyang Jieyu prescription and fluoxetine regulated the abnormal state of the 5-HTergic nerve and HPA axis. Compared with NC group， the modeling down-regulated the mRNA and protein levels of BDNF and TrkB in the hippocampus （P<0.05， P<0.01）， which， however， were recovered in Wenyang， Jieyu， Wenyang Jieyu， and fluoxetine groups （P<0.05， P<0.01）. ConclusionThe mouse model of depression induced by MS+RS may present the syndrome of Yang deficiency and liver depression. Wenyang Jieyu prescription may increase the content of hippocampal neurotransmitters by regulating the 5-HT system and the BDNF signaling pathway mediated by the HPA axis， thereby alleviating depression-like behavior in mice.

Dexmedetomidine improving complete Freund's adjuvant-induced anxiety-like and depression-like behaviour by promoting the expression of brain-derived neurotrophic factor-tyrosin kinase receptor B in mice hippocampus / 解剖学报

Objective To study the effect of dexmedetomidine (DEX), an α2- adrenoceptor agonist, on the pain-related anxiety-like and depression-like behaviour induced by complete Freund' s adjuvant (CFA) injection and its possible regulatory mechanism. Methods Thirty-six ICR female mice were randomly divided into normal saline (NS) group, CFA group and DEX + CFA group, n = 12 for each group. Chronic inflammatory pain model was established by subcutaneous injection of 10 μl CFA into the right hind limb of mice. DEX + CFA group mice were injected intraperitoneally with 0.025 mg/kg DEX 30 minutes before nociceptive behavior test, and once a day for 7 days. Von-frey fiber was used to evaluate the threshold of mechanical pain in mice, n = 12 for each group. The anxiety-like behavior of mice were detected by open field test, n = 12 for each group. Sucrose preference, tail suspension test and forced swimming test were used to detected the depression-like behavior of mice, n = 12 for each group. The expression of adrenergic receptor β2 (ADRB2), Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), and glutamate receptors 1 (GluR1) and GluR2 were detected by Western blotting, n = 8 for each group. Immunohistochemical staining was used to detect the expression of recombinant doublecortin(DCX), which is a marker of newborn neurons in the hippocampus, n = 4 for each group. Results Compared with the NS group, the mechanical threshold of mice on the 1st, 3rd and 7th day after CFA injection decreased significantly (P 0.05). Compared with the NS group, the time spent in the inner ares (P<0.01), number of entering the central grid area (P<0.01) and distance travelled in the inner area (P<0.01) of CFA group mice reduced significantly, while the time (P<0.01), numbers (P < 0.05) and distance (P < 0.05) of DEX + CFA group mice entering the central grid area enhanced significantly. The result of depression-like behavior tests showed that the sucrose preference percentage (P < 0.05) reduced significantly in CFA group when compared with NS group, and the immobility time increased significantly in tail suspension test (P<0.01) and forced swimming test (P< 0.001) in CFA mice when compared with NS group, while DEX intervention could significantly increase the sucrose preference scores (P<0.05) and decreased the immobility time in tail suspension test (P<0.05) and forced swimming test (P<0.05). The result of Western blotting showed that compared with the NS group, the levels of ADRB2 (P<0.0010), BDNF (P < 0.001), TrkB (P < 0.01), GluR1 (P < 0.001) and GluR2 (P < 0.001) in the hippocampus of CFA group were significantly decreased, while DEX intervention could significantly increase the expression of ADRB2 (P<0.05), BDNF (P < 0.001), TrkB (P < 0.001), GluR1 (P < 0.001) and GluR2 (P < 0.001). Immunohistochemical result showed that compared with the NS group, the average absorbance (AA) of DCX decreased significantly in hippocampus of CFA group (P<0.05), but increased significantly in DEX+CFA group (P < 0.05). Conclusion Dexmedetomidine may promote hippocampal neurogenesis through upregulated the expression of BDNF-TrkB, thus improving CFA-induced anxiety-like and depression-like behaviors in mice.

Exploración del efecto de Trichocereus pachanoi en el carácter depresivo en ratas / Exploring the effect of Trichocereus pachanoi on the depression-like behavior in rats

Introducción: Existen plantas que se usan desde tiempos ancestrales con efecto alucinógeno y alteraciones al sistema nervioso central, debido a la presencia principalmente de mezcalina son usadas para cumplir objetivos tradicionales asociados a la adivinación, curandería, divinidad y otros. Objetivos: Determinar el efecto del extracto acuoso de Trichocereus pachanoi a dosis de 10 por ciento, 20 por ciento y 30 por ciento sobre el comportamiento exploratorio de carácter depresivo en Rattus rattus var. albinus. Material y métodos: El presente estudio experimental es de carácter exploratorio aplicado, constructivo y prospectivo, se formaron 4 grupos de 10 ratas cada uno a las que se les administró extracto acuoso de Trichocereus pachanoi en dosis creciente, luego fueron sometidas a natación forzada con entrenamiento previo de 15 minutos. Resultados: El grupo que no recibió tratamiento alguno posee la más baja respuesta en gasto de tiempo para el escalamiento, comparado con los grupos B, C y D que presentan 13,5 min. 17,17 min. y 24,37 min. respectivamente. También en la evaluación de la movilidad, el grupo A posee en valor más bajo, comparado con los grupos B, C y D que presentan 13,42 min. 17,62 min. y 23,12 min., respectivamente. Conclusiones: El tratamiento en ratas con extracto acuoso de Trichocereus pachanoi a concentraciones de 10 por ciento, 20 por ciento y 30 por ciento ha sido eficaz en producir un efecto tranquilizante en el comportamiento exploratorio de carácter depresivo en el sujeto(AU)

Introduction: Since ancient times, some mescaline containing plants that have hallucinogen effects and cause alterations in the central nervous system have been used to fulfill traditional objectives associated with divination, healing, spirituality and others. Objective: To determine the effect of the aqueous extract of Trichocereus pachanoi at doses of 10 %, 20 % and 30 % solution on depression-like exploratory behavior in Rattus rattus var. albinus. Material and Methods: The present experimental study, which is exploratory, constructive and prospective in nature, was conducted in 4 groups of 10 rats. The rats were administered increasing doses of aqueous extract of Trichocereus pachanoi; then, they underwent forced swimming with a previous 15-minute training. Results: The group that did not receive any treatment had the lowest response to the duration of time spent at scaling compared to groups B, C and D that spent 13.5 min., 17.17 min., and 24.37 min., respectively. Also, in the evaluation of mobility, group A showed the lowest value compared to groups B, C and D that recorded 13.42 min., 17.62 min., and 23.12 min., respectively. Conclusions: The treatment with aqueous extract of Trichocereus pachanoi at concentrations of 10 percent, 20 percent and 30 percent applied to rats has been effective in producing a tranquilizer effect on the depression-like exploratory behavior in rats(AU)

Voluntary wheel running prevents the formaldehyde induced negative emotion through up-regulation of hippocampal neurogenesis in mice / 解剖学报

Objective To investigate the effect of voluntary wheel running on negative affective of mice induced by formaldehyde. Methods Thirty male Kunming mice were randomly divided into three groups, including normal saline control group (NS), formaldehyde model group (F), and voluntary wheel running with formaldehyde injection group ( R+ F). The pain model was established by right hindpaw intraplantar formalin injection, the mice of R+F group experienced voluntary wheel running for three weeks before intraplantar formaldehyde injection. The spontaneous pain behavior was determined by the cumulative time of licking paw. The anxiety-like behavior of each group was determined by open field test (OFT) and elevated plus-maze test (EPM) while the depression-like behavior of each group was determined by forced swimming test (FST). The expression of doublecortin ( DCX ) in the hippocampus was determined by immunohistochemistry. Results Compared with the NS group, the typical two-phase pain response was observed in the F group, and compared with the F group, the second phase pain duration was significantly reduced in the R+F group (P<0. 01). In the open field test, the F group showed remarkably reduced time in the inner area(P<0. 001) compared with the NS group, while the R+F group increased time in the inner area (P<0. 05) compared with the F group. In the elevated plus-maze test, the F group showed remarkably reduced time (P< 0. 001) spent in the open arm compared with the NS group, however, compared with the F group, R+F group increased time spent in the open arm (P<0. 05). In the forced swimming test, the immobility time of the F group significant increased (P<0. 01) compared with the NS group, which was decreased in the R+F group (P<0. 05). The Immunohistochemistry showed that the area of DCX positive cells in the hippocampus of the F group was downregulated compared with the NS group, which was upregulated in the R+F group. Conclusion Our findings indicate that voluntary wheel running can improve anxiety and depression-like in mice induced by formaldehyde injection, which may be related to enhanced neurogenesis in the hippocampus.

Actions of progesterone on depression-like behavior in a model of surgical menopause are mediated by GABAA receptors / Las acciones de progesterona sobre la conducta tipo depresión en un modelo de menopausia quirúrgica son mediadas por receptores GABAA

Abstract Introduction In rats, long-term ovariectomy results in low concentrations of steroid hormones and reproduces anxiety- and depression-like behavior after surgical menopause in women. Progesterone produces antidepressant-like effects two weeks post-ovariectomy (i.e., early post-ovariectomy) through actions on γ-aminobutyric acid-A (GABAA) receptors, but its antidepressant-like effects and mechanism of action in rats eight weeks post-ovariectomy (i.e., late post-ovariectomy, considered a model of surgical menopause) remain unknown. Objective To explore the antidepressant-like effects of progesterone and the participation of GABAA receptors in rats eight weeks post-ovariectomy. Method Long-term ovariectomized female Wistar rats were treated sub-acutely with vehicle or progesterone (.5, 1, and 2 mg/kg) and subjected to the open field and forced swim tests, and behavior was compared with cycling or fluoxetine-treated rats. The rats were then pretreated with picrotoxin (1 mg/kg) followed by progesterone (1 mg/kg) to explore the role of GABAA receptors in long-term-induced depression-like behavior. Results Long-term ovariectomized rats exhibited depression-like behavior in the forced swim test compared with intact rats, an effect that was not observed in progesterone- and fluoxetine-treated long-term ovariectomized rats. These effects were not attributable to psychomotor alterations. In the open field test, the time spent rearing and grooming was lower in ovariectomized rats compared with intact rats, which was not observed in progesterone- and fluoxetine-treated rats. Picrotoxin blocked the effects of progesterone in both behavioral tests. Discussion and conclusion These results indicated that sub-acute progesterone treatment reduced depression-like behavior through actions on GABAA receptors in a rat model of surgical menopause.

Resumen Introducción En la rata, la ovariectomía a largo plazo reproduce algunos síntomas de la menopausia quirúrgica, incluyendo la conducta de tipo depresiva. La progesterona produce efectos tipo antidepresivo en ratas con dos semanas de post-ovariectomía (post-ovariectomía temprana) con participación del receptor GABAA, pero se desconoce si este efecto y mecanismo de acción se mantiene en ratas con ocho semanas de post-ovariectomía (post-ovariectomía tardía considerada como un modelo de menopausia quirúrgica). Objetivo Evaluar el efecto tipo antidepresivo de la progesterona y la participación del receptor GABAA en ratas con ocho semanas de post-ovariectomía. Método Ratas con ocho semanas de post-ovariectomía fueron tratadas sub-agudamente con vehículo o progesterona (.5, 1, y 2 mg/kg) y comparadas con ratas intactas u ovariectomizadas tratadas con fluoxetina, evaluadas en campo abierto y nado forzado. Posteriormente, se identificó la participación del receptor GABAA en los efectos de progesterona (1 mg/kg) mediante el pretratamiento con picrotoxina (1 mg/kg). Resultados En nado forzado, la ovariectomía produjo conductas tipo depresión en comparación con las ratas intactas de la gónada, un efecto prevenido por la administración de progesterona y fluoxetina. En campo abierto, no hubo cambios significativos en la locomoción, pero la conducta vertical y el acicalamiento fueron bajos en las ratas ovariectomizadas respecto a las ratas intactas; lo cual fue prevenido por progesterona y fluoxetina. La picrotoxina bloqueó los efectos de la progesterona en ambas pruebas conductuales. Discusión y conclusión El tratamiento subagudo con progesterona reduce la conducta tipo depresión inducida en un modelo de menopausia quirúrgica con participación del receptor GABAA.

Chronic injection of corticosterone induces depression and impairment of learning and memory in mice / 中国比较医学杂志

Objective To Study the depression-like behavior and impairment of learning and memory induced by chronic injection of corticosterone in mice. Methods Forty male C57BL/6J mice were divided into four groups, the control group, and the corticosterone groups(20,40,80 mg/kg). The mice received subcutaneous injection of corticosterone once a day for 21 days. The depression-like behaviors were detected by open field test(OFT), tail suspension test(TST)and forced swimming test(FST). To select the most effective dose of corticosterone, TST, FST, object location recognition test, and Morris water maze(MWM)test were used to study the corticosterone-induced depression-like behaviors and impairment of learning and memory in the mice. Results Compared with the control group, the movement distance and duration were significantly decreased in the corticosterone injection groups(40,80 mg/kg)(P< 0.01 or P< 0.05). In the TST group,the immobilization time was significantly increased in the corticosterone injection group(40,80 mg/kg)(P< 0.05). The TST and FST showed that the immobilization time of the corticosterone injection group(40 mg/kg)was significantly increased(P < 0.05). The object recognition test showed that the discrimination indexes of the object location recognition were decreased in the corticosterone injection group(40 mg/kg). The MWM test showed that the escape latency was increased(P< 0.05),and the number of crossing in target quadrant and the velocity in target quadrant were decreased(P< 0.05)in the corticosterone injection group(40 mg/kg). Conclusions Chronic injection of corticosterone can induce depression accompanied with learning and memory impairment in mice.

Effects of ketamine on depression-like behaviors of male offspring rat exposed to prenatal restraint stress / 中华行为医学与脑科学杂志

Objective To investigate the effect of ketamine on depression-like behaviors at different developmental stages of offspring rat exposed to prenatal restraint stress (PRS).MethodsPregnant SD rats were randomly divided into control group (n=6) and PRS group (n=8).The dams of PRS group received three times(45 minutes/time)restraint stress every day.The anxiety-like and depression-like behaviors of the offsprings of the two groups were tested in the stage of juvenile,adolescence and early adulthood.Then the antidepressant effect of ketamine on prenatal stress rats at different developmental stages was observed.ResultsIn the open-field test,the time in the central area of the offspring rats in PRS group at different developmental stages (juvenile(2.50±0.43)s,adolescence(9.17±1.05)s,early adulthood(8.33±0.92)s) were significantly lower than those of the control group((8.33±1.05)s,(19.17±1.06)s,(18.83±1.30)s,all P<0.05).In the forced swimming test,the immobility time in the offspring rats of PRS group at the different developmental stages (juvenile(192.50±10.82)s,adolescence(182.75±10.12)s,early adulthood(199.88±9.20) s)were significantly higher than those of control group((76.00±19.00)s,(96.30±12.91)s,(108.30±10.98)s,all P<0.05).Ketamine could quickly and strongly reduce the immobility time of the offsprings exposed to PRS in the stage of adolescence and early adulthood (P<0.01),but the effect was weaker in the juvenile offsprings (P<0.05).ConclusionPRS leads to persistent anxiety-like and depression-like behavior in offsprings and ketamine exerts a good antidepressant effect on the offspring rats in the stage of adolescence and early adulthood.

Effect of maternal separation stress on behavior of neonatal rd mice / 中国比较医学杂志

Objective To evaluate the effect of maternal separation stress on the behavior of neonatal rd mice.Methods Neonatal rd mice were divided into maternal separation (MS) group (n=9) and control group (n=9).MS-stress was induced in the MS group by 4-hour-separation per day for 28 days.Open field test,elevated plus maze test,forced swim test and tail suspension test were used to evaluate the anxiety-like and depression-like behavior of the neonatal rd mice.Results The stay time and distance travelled of MS group in the central zone were 0.88％ and 28.17±5.65 cm,respectively,significantly shorter than that of the control group (2.61％,109.9±9.79 cm.P =0.04,P =0.001).Compared with the control group,the stay time in open arms of the MS group was significantly decreased (P<0.01),while the immobility time in forced swim test and tail suspension test of the MS group were 126.5±10.22 s and 21.56±6.83 s,significantly longer than that of the control group (77.75±16.83 s,P =0.02,7.37±3.22 s,P =0.03).Conclutions The 28-day maternal separation stress can significantly increase the anxiety-like and depression-like behavior in neonatal rd mice.

Mechanism Study of Xiaoyao San in Improving Depression-Like Behavior of Rats by Regulation of Hepatic Sinusoidal Endothelial Function / 广州中医药大学学报

Objective To observe the effectiveness and mechanism of Xiaoyao San (Xiaoyao Powder for Soothing Liver and Relieving Depression) in improving depression-like behavior of rats. Methods Male Wistar rats were randomized into normal group, model group, Xiaoyao San (1.9 g·kg-1·d-1) group, and fluoxetine (2 mg·kg-1·d-1) group. The rats were exposed to chronic unpredictable mild stress ( CUMS) to induce rat depression-like behavior. Field test was performed for the observation of effect of Xiaoyao San on rat depression-like behavior, Luminex liquid chip system was applied to detect the serum cytokines, and the amount and size of rat hepatic sinusoidal endothelial window were examined under electron microscope, and hepatic indoleamine 2, 3-dioxygenase ( IDO) and tryptophan 2, 3 -dioxygenaes ( TDO) expression levels were detected by immunohistochemical and Western blot methods. Results Xiaoyao San showed obvious effect on increasing sugar water consumption, the number of crossing the blocks and erection frequency in rats, decreasing serum levels of tumor necrosis factor alpha ( TNF-α) and interleukin 6 ( IL-6) , increasing the amount of hepatic sinusoidal endothelial window, promoting hepatic sinusoidal endothelial vascularization, and reducing TDO and IDO expression ( P<0.05 or P<0.01). Conclusion Xiaoyao San exerts obvious effect on improving rat depression-like behaviors, and the mechanism is probably related with the decrease of inflammatory factors, inhibition of IDO pathway, and improvement of hepatic sinusoidal endothelial function.

Effect of long-term chronic mild stress on depression-like behavior and the expression of heat shock protein 70 in rats / 中华行为医学与脑科学杂志

Objective To explore the effect of long-term chronic mild stress on depression-like behaviors and the expression of heat shock protein 70(HSP70) in rats.Methods The standard SD rats were divided into two groups as following:one group (n =6) was treated with chronic mild stress for 3 weeks,and another group (n =5) was treated with chronic mild stress for 6 weeks.Depression-like behaviors of rats was observed by sucrose consumption test and open field test before and after chronic mild stress.And Western Blot,RT-PCR and immunohistochemistry were utilized to detect the HSP70 expression in the hippocampus and frontal lobes of rats after chronic mild stress.Results The sucrose favoritism in sucrose consumption test,the scores of crossing and the time for rats' retention in the center grid of open field test in long-term group were higher than those in short term group(P＜ 0.05).HSP70 expression in the hippocampus and frontal lobes of long-term group (0.81 ± 0.08,0.85 ± 0.08)detected by Western Blot and immunohistochemistry was higher that of short-term group (0.60 ± 0.06,0.85 ±0.07).HSP70 expression in the hippocampus of long-term group (0.90 ± 0.05,1.37 ± 0.38)detected by RT-PCR was higher that of short-term group(0.78 ± 0.04,1.08 ± 0.14) (P ＜ 0.05).Conclusion After long-term chronic mild stress,the depression-like behaviors decrease,and at the same time HSP70 mRNA and protein increase.

The difference among the depression-like behaviours induced by three widely-used stress models in rats / 中华行为医学与脑科学杂志

Objective In order to study the difference of depression-like behaviours among three widelyused stress models in rats.Methods The new-born Spragne-Dawley rats were randomly divided into maternal deprivation(MD) group(n=27),chronic mild stress(CMS) group (n=29),dual stress(DS) group ( n=31 ) and control (C) group ( n =30) on postnatal day 1.MD rats only received maternal deprivation.CMS rats only received chronic mild stress when 10 weeks old.DS rats received both maternal deprivation and chronic mild stress.Control rats received no experimental handling.Behavior tests including forced swimming test and sucrose consumption which were carried out to evaluate rats' depression-like behaviors in the thirteenth weeks.The extend time of floating and sucrose preference ratio should be recorded in the forced swimming test and sucrose consumption test respectively to reflect the behavior of helplessness and anhedonia of rats.Results In the forced swimming test,the extend floating time of MD group( 119.30 ± 65.56) s,CMS group ( 145.00 ± 80.24) s and DS group ( 170.03 ±61.75 )s were longer than the control group(81.14 ± 52.40)s (F =11.53,P ＜ 0.01 ).In the sucrose consumption test,the MD group(0.32 ± 0.22) had a low sucrose consumption.The comparison of the MD group and CMS group (0.43 ± 0.28 ) to the control group (0.54 ± 0.28 ) had significant differences (F =4.33,P ＜ 0.01 ).In these four groups,no sexual difference was found in the forced swimming test and sucrose consumption test ( all P ＞ 0.05 ).Conclusion The results suggest that MD,CMS and DS may induce some kind of depression-like behaviors in rodents such as anhedonia or the behavior of helplessness and the depression-like behaviors induced by different stresses are similar in male and female individuals.