Study on the antidepressant activity of (2R,6R; 2S,6S)-Hydroxynorketamine (HNK) and its derivatives

Abstract Objective: This study mainly explores (2R,6R; 2S,6S)-HNK and its compounds whether there are antidepressant effects. Methods: Four HNK compounds were obtained from 2-(Chlorophenyl) Cyclopentylmethanone. Forced swimming test, locomotor sensitization test, and conditioned location preference test were used to screen the antidepressant activity of the synthesized target compounds. Results: In the case of 10 mg HNK treatment, compared with saline, the immobile time of mice in the HNK group, I5 group and I6 group at 1 h and 7 days had statistical significance. In the case of 10 mg HNK treatment, compared with saline, the immobile time of compound C and D groups in the glass cylinder area was significantly different. In the locomotor sensitization test, the movement distance of compound C and D groups on day 15 and day 7 mice increased significantly compared with the first day. In the conditioned place preference experiment, compound C and compound D induced conditioned place preference in mice compared with the Veh group. Conclusion: The results of the forced swimming test, locomotor sensitization test, and conditioned location preference test showed that compounds C and D may have certain anti-depressant activity. However, HNK exerts a rapid and significant antidepressant effect within 1 week, but the duration is short.

ANTIDEPRESSANT-LIKE ACTIVITY OF METHANOLIC EXTRACT OF WITHANIA QARAITICA IN MICE

Objective: The goal of the present study was to assess the antidepressant-like action of Withania qaraitica in two behavioral animal models, the forced-swimming test (FST) and tail suspension test (TST) in mice.Methods: Withania qaraitica methanolic extract was prepared by the maceration. The antidepressant activity was measured by the forced-swimming test (FST) using C57BL/6 mice and the tail suspension test (TST) using BALB/c mice. Mice were divided into three groups: control (DMSO), standard (citalopram and desipramine), and Withania qaraitica methanolic extract (n = 6 per group). Drugs were injected (1 ml/100 g) intraperitoneally (i. p.). Data were evaluated using analysis of variance, followed by LSD post-hoc tests, where *p<0.001 was considered significantly different from the vehicle control. The data are expressed as mean±SEM.Results: In both the FST and the TST, antidepressant-positive controls citalopram and desipramine significantly reduced the time of immobility compared to vehicle control (p<0.001). The methanolic extract of Withania qaraitica at the dose of 40 mg/kg significantly reduced the immobility times with respect to vehicle control as well as lower doses of the same extract (10 and 20 mg/kg) in FST (p<0.001). In a similar fashion, the methanolic extract of Withania qaraitica at the dose of 40 mg/kg significantly decreased the duration of immobility in TST (p<0.005).Conclusion: The current results show the antidepressant-like activity of Withania qaraitica in mice. This observation warrants additional studies to identify the underlining mechanism by which Withania qaraitica produces antidepressant-like effects.

Rapid and long-lasting antidepressant-like effects of ketamine and their relationship with the expression of brain enzymes, BDNF, and astrocytes

Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug's sustained antidepressant-like effects.

Astrocytic GABA Receptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF / 神经科学通报·英文版

Major depressive disorder (MDD) is a common mood disorder that affects almost 20% of the global population. In addition, much evidence has implicated altered function of the gamma-aminobutyric acid (GABAergic) system in the pathophysiology of depression. Recent research has indicated that GABA receptors (GABARs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD. However, which cell types with GABARs are involved in this process is unknown. As hippocampal dysfunction is implicated in MDD, we knocked down GABARs in the hippocampus and found that knocking down these receptors in astrocytes, but not in GABAergic or pyramidal neurons, caused a decrease in immobility in the forced swimming test (FST) without affecting other anxiety- and depression-related behaviors. We also generated astrocyte-specific GABAR-knockout mice and found decreased immobility in the FST in these mice. Furthermore, the conditional knockout of GABARs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes, which controlled the decrease in immobility in the FST. Taken together, our findings contribute to the current understanding of which cell types expressing GABARs modulate antidepressant activity in the FST, and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.

Effects of Liuwei Dihuang Decoction (Yukmijihwang-tang) on Physical Fatigue by Regulating Neurotransmitters in Brain / 中国结合医学杂志

OBJECTIVE@#To study the effect of Liuwei Dihuang Decoction () or Yukmijihwangtang (YJT) on endurance exercise by in vivo experiment.@*METHODS@#ICR mice were randomly divided into the control group (distilled water) and the YJT groups (1, 10, 100 mg/kg), 5 animals per group. YJT and distilled water were orally administered. The anti-fatigue effect of YJT was evaluated by open fifiled test (OFT), forced swimming test (FST), and tail suspension test (TST).@*RESULTS@#In the OFT, YJT signifificantly increased the total movement distance in a dose-dependent manner. Additionally, treatment with YJT signifificantly decreased immobility time in the FST and the TST. Various neurotransmitters such as norepinephrine (NE), serotonin (5-HT), dopamine (DA) levels were increased by FST. Administration of YJT down-regulated the expression levels of NE, 5-HT, 5-hydroxyindole-acetic acid (5-HIAA), and DA in the brain stem and hypothalamus of mice. Moreover, protein expression of HSP70 in mice liver and heart muscles was signifificantly increased in the YJT groups.@*CONCLUSIONS@#YJT could ameliorate fatigue and enhance exercise tolerance through suppressing of brain monoamines including NE, 5-HT, 5-HIAA, and DA in FST mice model.

Evaluation of antidepressant activity of tramadol in albino mice using forced swim model

Background: The fact that tramadol can be used as an antidepressant, has been already proved by some animal studies. The objective of the present study was to evaluate antidepressant activity of tramadol in albino mice using forced swim model.Methods: Forced swimming test (FST) model was used to evaluate the antidepressant effect. Mice in the group "I" were given normal saline. Mice in the group II were given imipramine. Mice in the group III were given tramadol 10mg/kg. Mice in the group IV were given tramadol 20mg/kg. Mice in the group V were given tramadol 40mg/kg. All doses in all groups were given by intra peritoneum route.Results: The average values of immobility in group I were higher significantly compared to group III, IV and V. The values of group I and group II were found to be comparable. It was found that the baseline mean value was 196.33 which reduced to 5.16 with the effect of imipramine where imipramine was given to those mice. But in tramadol 10mg group, it was highest, and it came down to 40.66 and as the dose of tramadol was increased, the immobility time reduced from 40.66 at 10mg dose to 31.33 at 20mg dose and finally to 13.33mg at 40mg dose.Conclusions: Considering the results of two different animal models of depression it can be concluded that Tramadol has antidepressant activity at 10mg, 20mg, 40mg which was almost similar to Imipramine.

Effect of Hypericum Perforatum L Extracts on depression induced by chronic unpredictable mild stress in mice / 中华行为医学与脑科学杂志

Objective To observe the improving effect of Hypericum Perforatum L Extracts (HPLES)on depression induced by chronic unpredictable mild stress in mice. Methods The depression model was established by the method of chronic unpredictable mild stress. Fifty depression model mice were divided into model control group,fluoxetine hydrochloride group (2. 6 mg / kg),Hypericum perforatum ex-tract low,medium and high (0. 2 g / kg,0. 4 g / kg,0. 8 g / kg) dose groups according to the random num-ber table method. Another 10 normal mice matched with body weight were taken as the normal control group. The mice in normal control group and the model control group were given pure water by gavage every day,and the mice in other groups were given corresponding solution by gavage for 4 weeks. In addition to the normal control group,the mice in other groups continued to undergo chronic unpredictable mild stress during gavage. The sugar water preference test and forced swimming test were performed after the last administration. Blood samples were collected from the posterior orbital venous plexus,and the levels of dopamine (DA) and brain-derived neurotrophic factor (BDNF) were measured by Elisa. The hippocampal tissues of mice were exam-ined by HE staining. Results Compared with the normal control group,the body mass of mice in the model control group decreased significantly at the first,second,third and fourth weeks ( t=2. 739,4. 162,4. 082, 3. 957;all P<0. 05). At the first,second,third and fourth weeks,the body mass of mice in the low,middle and high dose group of Hypericum perforatum extract were not significantly different from those in the model control group (all P>0. 05). Compared with the normal control group,the sugar water preference index of mice in the model control group was significantly reduced((61. 3± 4. 5)%,(52. 6± 5. 2)%; t=2. 721,P<0. 05),the swimming immobility time was prolonged(( 44. 3± 20. 00) s,(101. 8± 50. 8) s;t=2. 939,P<0. 05),the difference were statistically significant. Compared with the model control group,the sugar water preference index of mice in the low,middle and high dose group of Hypericum perforatum extract increased ((61. 8±4. 7)%,(65. 2±4. 1)%,(62. 6±5. 6)%,t=-3. 005,5. 073,-2. 928,all P<0. 05),the swimming immobility time decreased ((47. 2±17. 9) s,(54. 8±50. 3) s,(61. 3±44. 2) s; t=2. 803,1. 921,1. 903,all P<0. 05). The results of Elisa showed that compared with the normal control group,the levels of serum DA and BDNF of mice in the model control group were significantly lower (t=3. 031,8. 507,all P<0. 05); com-pared with the model control group,the levels of serum DA of mice in the low dose and high dose group of Hypericum perforatum were significantly higher (t=5. 025,3. 414,P<0. 05),and the serum BDNF of mice in the high dose group of Hypericum perforatum was also significantly higher (t=6. 098,P<0. 05),the differ-ence was statistically significant. HE staining showed that compared with the normal control group,the neu-rons in CA3 area of hippocampus in the model control group mice were seriously damaged,suggesting the es-tablishment of the mouse model. Compared with the model control group,the atrophy and degeneration of hippocampal CA3 cells in the three dose groups were significantly reduced. The atrophy and deformation of hippocampal CA3 neurons in the low,middle and high dose groups of Hypericum perforatum extract were re-lieved. Conclusion HPLES have obvious improving and antidepressant effects on the depression model mice induced by chronic unpredictable stress. The above effects may be related to the improvement of serum DA,DBNF level and reduce neuronal damage in CA3 area.

Effect of Hypericum Perforatum L Extracts on depression induced by chronic unpredictable mild stress in mice / 中华行为医学与脑科学杂志

Objective@#To observe the improving effect of Hypericum Perforatum L Extracts (HPLES)on depression induced by chronic unpredictable mild stress in mice.@*Methods@#The depression model was established by the method of chronic unpredictable mild stress. Fifty depression model mice were divided into model control group, fluoxetine hydrochloride group (2.6 mg / kg), Hypericum perforatum extract low, medium and high (0.2 g / kg, 0.4 g / kg, 0.8 g / kg) dose groups according to the random number table method. Another 10 normal mice matched with body weight were taken as the normal control group. The mice in normal control group and the model control group were given pure water by gavage every day, and the mice in other groups were given corresponding solution by gavage for 4 weeks. In addition to the normal control group, the mice in other groups continued to undergo chronic unpredictable mild stress during gavage.The sugar water preference test and forced swimming test were performed after the last administration. Blood samples were collected from the posterior orbital venous plexus, and the levels of dopamine (DA) and brain-derived neurotrophic factor (BDNF) were measured by Elisa. The hippocampal tissues of mice were examined by HE staining.@*Results@#Compared with the normal control group, the body mass of mice in the model control group decreased significantly at the first, second, third and fourth weeks (t=2.739, 4.162, 4.082, 3.957; all P<0.05). At the first, second, third and fourth weeks, the body mass of mice in the low, middle and high dose group of Hypericum perforatum extract were not significantly different from those in the model control group (all P>0.05). Compared with the normal control group, the sugar water preference index of mice in the model control group was significantly reduced((61.3±4.5)%, (52.6±5.2)%; t=2.721, P<0.05), the swimming immobility time was prolonged((44.3±20.00) s, (101.8±50.8) s; t=2.939, P<0.05), the difference were statistically significant. Compared with the model control group, the sugar water preference index of mice in the low, middle and high dose group of Hypericum perforatum extract increased((61.8±4.7)%, (65.2±4.1)%, (62.6±5.6)%, t=-3.005, 5.073, -2.928, all P<0.05), the swimming immobility time decreased ((47.2±17.9) s, (54.8±50.3) s, (61.3±44.2) s; t=2.803, 1.921, 1.903, all P<0.05). The results of Elisa showed that compared with the normal control group, the levels of serum DA and BDNF of mice in the model control group were significantly lower (t=3.031, 8.507, all P<0.05); compared with the model control group, the levels of serum DA of mice in the low dose and high dose group of Hypericum perforatum were significantly higher (t=5.025, 3.414, P<0.05), and the serum BDNF of mice in the high dose group of Hypericum perforatum was also significantly higher (t=6.098, P<0.05), the difference was statistically significant. HE staining showed that compared with the normal control group, the neurons in CA3 area of hippocampus in the model control group mice were seriously damaged, suggesting the establishment of the mouse model. Compared with the model control group, the atrophy and degeneration of hippocampal CA3 cells in the three dose groups were significantly reduced. The atrophy and deformation of hippocampal CA3 neurons in the low, middle and high dose groups of Hypericum perforatum extract were relieved.@*Conclusion@#HPLES have obvious improving and antidepressant effects on the depression model mice induced by chronic unpredictable stress.The above effects may be related to the improvement of serum DA, DBNF level and reduce neuronal damage in CA3 area.

Evaluation of antidepressant activity of l-methylfolate per se and its interaction with escitalopram in mice

Background: Depression is a worldwide illness in the current population. Low levels of L-methylfolate are linked to depression. Present study evaluates the anti-depressive activity of acute and chronic administration of L-methylfolate per se in forced swimming test (FST) and tail suspension test (TST) and its interaction with escitalopram in albino mice.Methods: For this 30 swiss albino mice were divided randomly into five groups (n=6) as group I (control,10ml/Kg, p.o) - 2% suspension of gum acacia, group II - escitalopram suspension (10mg/kg, p.o), group III- L-methylfolate suspension (3mg/kg, p.o), group IV- L-methylfolate (3mg/kg, p.o) plus escitalopram (5mg/kg, p.o), group V- L-methylfolate(3mg/kg, p.o) plus escitalopram(10mg/kg, p.o), for forced swimming test. In tail suspension test again, mice were divided in five groups as above except that the dose of L-methylfolate was reduced to 1.25mg/kg. The pharmacologically validated models forced swimming test and tail suspension test were performed in mice to evaluate acute and chronic antidepressant activity of L-methylfolate and its combination with escitalopram respectively, after performing an acute toxicity study.Results: L-methylfolate and L-methylfolate plus escitalopram (10mg/Kg and 5mg/Kg, p.o) showed acute and chronic antidepressant activity in albino mice in FST and TST respectively. In human L-methylfolate is only active form of folic acid that readily crosses the blood brain barrier and utilized by the CNS. It regulates the bioavailability of critical cofactor BH4, required by enzymes synthesizing monoamines whose deficiency leads to depression.Conclusions: Hence, this study suggests antidepresant activity of L-methylfolate per se and as adjuvant with escitalopram when initiated from initiation of antidepressant therapy. Also, L-methylfolate opens the possibility of reducing the dose of antidepressant when used as adjuvant.

Measurement and analysis of the behavioral changes of Rncat congenital cataract mice / 中国比较医学杂志

Objective To measure and analyze the behavioral changes of Rncat congenital cataract mice. Methods Normal BALB/c mice and KM mice were used as control group,and inbred and random mated Rncat congenital cataract mice were used as experimental group. Behavioral tests, including the open field test, coat-hanger test, forced swimming test,and tail suspension test,were conducted on the mice. Results Compared with the inbred Rncat congenital cataract mice,the residence time in the open field test,the immobility time in the forced swimming test and tail suspension test of the BALB/c mice, randomly-mated Rncat congenital cataract mice and KM mice were significantly different. Conclusions There are certain differences in behavioral performance between the Rncat congenital cataract mice and the other mice. Our findings may provide a useful reference for future researchers.

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.

Atividade antidepressiva do extrato etanólico da Kielmeyera Rubriflora Cambes (Pau Santo) em camundongos / Actividad antidepressiva del extracto etanolico de la Kielmeyera Rubriflora Cambes (Pau Santo) en ratones / Antidepressant activity of Kielmeyera Rubriflora Cambes (Pau Santo) ethanolic extract on mice

Introdução: a Kielmeyera rubriflora Cambess, pertencente à família Clusiacea, é uma planta nativa do Vale do Jequitinhonha em Minas Gerais no Brasil, onde é utilizada na medicina caseira. É conhecida como Pau Santo, Rosa do Campo, Flor de Santa Rita ou Rosa do Cerrado. Entretanto, até o momento não existem dados disponíveis na literatura no que diz respeito a estudos farmacológicos desta espécie. A Kielmeyera coriácea também é uma planta nativa da região e já existem estudos revelando sua ação antidepressiva. Objetivo: avaliar a ação antidepressiva do extrato etanólico das partes aéreas da K. rubriflora em camundongos. Método: o extrato etanólico das partes aéreas foi administrado por v.o. nas doses de 100 mg/kg, 250 mg/kg e 500 mg/kg em camundongos albinos, suíços, machos, com idade entre 9 e 13 semanas, com peso entre 29 e 43 g. Para a investigação dos efeitos antidepressivos foram utilizados os testes de triagem farmacológica comportamental (administração aguda), nado forçado (administração crônica) e suspensão da cauda (administração crônica). Resultados: na triagem farmacológica comportamental, foram detectados efeitos de depressão do sistema nervoso central pela dose de 100 mg/kg e de estímulo do sistema nervoso central nas doses de 250 e 500 mg/kg. No teste da suspensão da cauda houve diminuição dose-dependente, porém não significativa do tempo de imobilidade. No teste de nado forçado houve diminuição significativa do tempo de imobilidade em todas as doses investigadas sugerindo atividade antidepressiva, principalmente na dose de 100 mg/kg. Conclusão: os dados encontrados sugerem ação antidepressiva do extrato etanólico das partes aéreas da K. rubriflora(AU)

Introducción: la Kielmeyera rubriflora Cambess, perteneciente a la familia Clusiaceae, es una planta nativa del Valle de Jequitinhonha, en Minas Gerais en Brasil, donde se utiliza en la medicina popular. Se le conoce como Pau Santo, Rosa do Campo, Flor de Santa Rita o Rosa do Cerrado. Sin embargo, hasta ahora no hay datos disponibles en la literatura con respecto a los estudios farmacológicos de esta especie. La Kielmeyera coriacea es también una planta nativa de la región y ya hay estudios que revelan su acción antidepresiva. Objetivo: evaluar la acción antidepresiva del extracto crudo de las partes aéreas de la K. rubriflora en ratones. Método: el extracto crudo de las partes aéreas se administró v.o. en dosis de 100 mg/kg, 250 mg/kg y 500 mg/kg en ratones albinos, suizos, machos, con edades comprendidas entre 9 y 13 semanas, con un peso entre 29 y 43 g. Para la investigación de los efectos antidepressivos se utilizaron pruebas de screening farmacológico de comportamiento (administración aguda), nado forzado (administración crónica) y suspensión de la cola (administración crónica). Resultados: en el screening farmacológico de comportamiento se detectaron efectos de depresión del sistema nervoso central por la dosis de 100 mg/kg y estimulación del sistema nervoso central con las dosis de 250 y 500 mg/kg. En el ensayo de suspensión de cola hubo una disminución dependiente de la dosis, pero no significativa en el tiempo de inmovilidad. En la prueba de nado forzado hubo una disminución significativa en el tiempo de inmovilidad en todas las dosis investigadas, sugiriendo actividad antidepresiva, en particular a una dosis de 100 mg/kg. Conclusión: los resultados sugieren la acción antidepresiva del extracto crudo de las partes aéreas de la K. rubriflora(AU)

Introduction: The Kielmeyera rubriflora Cambess, belonging to the Clusiaceae family, is a native to the Vale do Jequitinhonha in Minas Gerais in Brazil, where it is used in folk medicine. It is popularly known as Pau Santo, Rosa do Campo, Flor de Santa Rita and Rosa do Cerrado. However, so far there are no data available in the literature on pharmacological studies regarding this species. The Kielmeyera coriácea is also a native plant in the region and there are already studies revealing its antidepressant action. Objective: To evaluate the antidepressant action of the crude extract fron the aerial parts of K. rubriflora in mice. Method: The crude extract from the aerial parts was administered v.o. at doses of 100 mg/kg, 250 mg/kg and 500 mg/kg in albino Swiss, male mice, between 9 and 13 weeks of age, weighing between 29 and 43 g. In order to the investigation of antidepressant effects, the behavioral pharmacological screening (acute administration), forced swimming (chronic administration) and tail suspension (chronic administration) tests were performed. Results: In the behavioral pharmacological screening were detected central nervous system depression effects with the dose of 100mg/kg and central nervous system stimulation with the doses of 250 and 500 mg/kg. In the tail suspension test, a dose-dependent, but not significant, decrease in the immobility time was observed. In the forced swimming test a significantly lower immobility time was observed at all doses investigated, suggesting an antidepressant activity, especially at a dose of 100 mg/kg. Conclusion: The results suggests an antidepressant action of the crude extract fron the aerial parts of K. rubriflora(AU)

Delay in Normalization of Disrupted Sleep-Wake Cycle in Mice as a Bipolar Disorder-Prone Animal Model (Bipolar Disorder-Prone Animal Model) / 신경정신의학

OBJECTIVES: This study was designed to test the hypothesis that delayed recovery from disrupted circadian rhythm is associated with both manic and depressive episodes in bipolar disorder. METHODS: Twenty-two male mice (age of five weeks, weight 28–30 gm) underwent three days of light-dark cycle disruption and 10 days of recovery phase. Sleep and wake state were checked every five minutes during the entire experimental period. After recovery phase, quinpirole (0.5 mg/kg, s.c.) was injected into the mice and open field locomotor activities were checked. Five days after the open field test, immobility time during the last 4 min in 6 min of forced swimming test was measured. Animals which recovered sleep-wake cycle within six days after light-dark cycle disruption were assigned to the early recovery group (n=14), and those that failed to recover in six days were assigned to the delayed recovery group (n=8). The locomotor activities and the immobility times of the two groups were compared by Mann-Whiney U test at two-tailed significance level of 0.05. RESULTS: The locomotor activities of the delayed recovery group were higher (mean rank=16.19) than those of the early recovery group (mean rank=8.82, U=18.5, p=0.008). The immobility times did not differ by recovery time (U=32.0 p=0.110). CONCLUSION: The results suggest that delayed recovery from circadian rhythm disruption raises the risk of manic symptoms rather than depressive symptoms.

Effect of no-ginsenoside argininyl-fructoyl-glucose in red ginseng on mice's fatigue and immunizition / 中国药学杂志

OBJECTIVE: To investigate the preliminary mechanism of no-ginsenoside small molecular component AFG (argininyl-fructoylglucose) in red ginseng to mice's immune and anti-fatigue by forced swimming. METHODS: Massive AFG was separated from red ginseng and was made powder (RM) by vacuum freeze drying machine. ICR mice were randomly divided into 4 groups; the control group (CG), low dose group (RM-LG, 100 mg·kg-1), medium dose group (RM-MG, 200 mg·kg-1), high dose group (RM-HG, 400 mg·kg-1), forced swimming test was made after continuous intragastric administration 28 d, and the mice's weight was tested; organ index, time of forced swimming, volume of lactic acid (LD), urea nitrogen (BUN), hepatic glycogen (Gly), antioxidant enzyme in serum, ability of spleen lymphocyte proliferation, CD3, CD4, CD8 levels in spleen lymphocyte, releasing volume of immune factor were determined. RESULTS: Compared with control group, weight and organ index of mice aren't significant difference in treatment group; the force swimming time of treatment group is significantly increased (P<0.01); volume of LD, BUN and MDA in serum of treatment group are significantly reduced (P<0.01), volume of Gly, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in serum of treatment group are significantly increased (P<0.01); releasing volume of IL-2 and IgG in serum of treatment group are significantly increased (P<0.01); ability spleen lymphocyte proliferation and CD3, CD4, CD8 levels in spleen lymphocyte are significantly increased (P<0.05) at treatment group. CONCLUSION: AFG has the effect of anti-fatigue and improving immunity in mice.

Spirit Behavioral Changes of Mental Disorders Caused by Traumatic Brain Injury in Rats / 中国医科大学学报

Objective To set up traumatic brain injury(TBI)in rats by the improved device of FEENEY ’s weight dropping model and to ex?plore the spirit behavioral changes of mental disorders caused by TBI. Methods SD rats were randomly divided into normal control group(normal group,n=10),traumatic brain injury group(TBI group,n=10)and sham group(n=10). The improved device of FEENEY’s method was ad?opted to establish rat TBI model. For the following 15 days after TBI,open?field(OF)and forced swimming(FS)tests were carried out and the be?havior of the TBI rats within 5 minutes were recorded,the behavioral indexes,such as distance moved total(DMT),velocity mean(VM)and immo?bility time total(ITT),were analyzed. With above experiments,rats' fear response to environment,high alertness and anxiety and depression be?havior were evaluated. Results DMT and VM of TBI group rats(1 228.10±204.97 cm,4.09±0.68 cm/s)were significantly lower than those of the normal group(2 022.32±280.92 cm,7.28±1.80 cm/s)or sham group(1 660.01±332.09 cm,5.53±1.10 cm/s)(P<0.05).The ITT of TBI group (149.88±27.36 s,P<0.05)was longer than that of the normal group(106.10±29.03 s)or sham group(120.55±22.31 s)significantly(P<0.05). Conclusion TBI leads to rats' abnormal emotional and behavioral response.

G-protein activation revealed by [35S]-GTPγS binding assay is involved on the antidepressant-like effect of Hyperi cum caprifoliatum and Hypericum polyanthemumcyclohexane extracts

AbstractPrevious studies by us demonstrated the antidepressant-like and antinociceptive effects of lipophilic extracts and dimeric acyl-phloroglucinols from species of the genus Hypericum native to Southern Brazil. Uliginosin B and HC1 (an enriched phloroglucinol fraction from Hypericum caprifoliatum) are able to inhibit monoamine synaptosomal uptake without binding to the monoaminergic sites on neuronal transporters, unlike classical antidepressants. The current study aimed at investigating the action of H. caprifoliatum Cham. & Schltdl. and Hypericum polyanthemum Klotzsch ex Reichardt, Hypericaceae, cyclohexane extracts and their main component, HC1 and uliginosin B, on G protein coupled receptors by using the [35S]-guanosine-5′-O-(3-thio)triphosphate ([35S]-GTPγS) binding assay, which reveals the G protein activity. The antidepressant-like effect of acute (one or three treatments within 24 h) and repeated (five days with and without a three day wash-out) treatments with the cyclohexane extracts was evaluated using the rat forced swimming test. The [35S]-GTPγS binding to monoamines and opioid receptors stimulated by agonists was performed ex vivo in brain membranes of rats acutely or repeatedly treated with the cyclohexane extracts. The effect of HC1 and Uliginosin B on [35S]-GTPγS binding assay was performed by direct incubation with brain membranes in the absence of agonists. Their antidepressant-like effect was evaluated through the mice forced swimming test. The extracts, HC1 and Uliginosin B showed antidepressant-like effect in the forced swimming test. The acute treatments with extracts increased the [35S]-GTPγS binding stimulated by the monoamines, while after five days of treatment the [35S]-GTPγS binding was reduced even after three day wash-out. These effects are not due to HC1 or Uliginosin B interaction with the receptors, since direct incubation with these phloroglucinols did not affect [35S]-GTPγS binding to membranes. Our findings indicate that H. caprifoliatum and H. polyanthemumextracts bring about adaptive changes in monoamine receptors, which reinforces their antidepressant-like profile.

Tamoxifen antagonizes the effects of ovarian hormones to induce anxiety and depression-like behavior in rats / Tamoxifeno antagoniza os efeitos dos hormônios ovarianos que induzem comportamento similar a ansiedade e depressão em ratos

The effects of tamoxifen (TAM) on anxiety and depression-like behavior in ovariectomized (OVX) and naïve female rats were investigated. The animals were divided into Sham-TAM, OVX-TAM, Sham and OVX groups. Tamoxifen (1 mg/kg) was administered for 4 weeks. In the forced swimming test, the immobility times in the OVX and Sham-TAM groups were higher than in the Sham group. In the open field, the numbers of central crossings in the OVX and Sham-TAM groups were lower than the number in the Sham group, and the number of peripheral crossings in the OVX group was lower than the number in the Sham group. In the elevated plus maze, the numbers of entries to the open arm among the animals in the Sham-TAM and OVX groups were lower than the number in the Sham group, while the number of entries to the open arm in the OVX-TAM group was higher than the number in the OVX group. It was shown that deletion of ovarian hormones induced anxiety and depression-like behavior. Administration of tamoxifen in naïve rats led to anxiety and depression-like behavior that was comparable with the effects of ovarian hormone deletion. It can be suggested that tamoxifen antagonizes the effects of ovarian hormones. It also seems that tamoxifen has anxiolytic effects on ovariectomized rats.

Foram investigados os efeitos do tamoxifeno (TAM) no comportamento semelhante a ansiedade de depressão de ratas ooforectomizadas (OVX) e controles. Os animais foram divididos em Sham-TAM, OVX-TAM, Sham e OVX groups. Tamoxifeno (1 mg/kg) foi administrado por quatro semanas. No teste de natação forçada, os tempos de imobilidade nos grupos OVX e Sham-TAM foram maiores que aqueles do grupo Sham. No campo aberto, os números de cruzamento no centro nos grupos OVX e Sham-TAM foram menores que aquele do grupo Sham, e o número dos cruzamentos na periferia no grupo OVX foi menor que o número no grupo Sham. No labirinto elevado, os números de entradas com braços abertos entre os animais nos grupos Sham-TAM e OVX foram menores do que aqueles do grupo Sham, enquanto o número de entradas com os braços abertos no grupo OVX-TAM foi maior que aquele no grupo OVX. Foi observado que a deleção dos hormônios ovarianos induziu comportamento similar a ansiedade e depressão. A administração de tamoxifeno em ratos controle induziu a um comportamento que era comparável aos efeitos da deleção do hormônio ovariano. Pode ser sugerido que o tamoxifeno antagoniza os efeitos dos hormônios ovarianos. Parece também que o tamoxifeno tem efeito ansiolítico nas ratas ooforectomizadas.

Antidepressant-like effect of Hoodia gordonii in a forced swimming test in mice: evidence for involvement of the monoaminergic system

Hoodia gordonii is a plant species used traditionally in southern Africa to suppress appetite. Recently, it has been associated with a significant increase in blood pressure and pulse rate in women, suggesting sympathomimetic activity. The present study investigated the possible antidepressant-like effects of acute and repeated (15 days) administration of H. gordonii extract (25 and 50 mg/kg, po) to mice exposed to a forced swimming test (FST). Neurochemical analysis of brain monoamines was also carried out to determine the involvement of the monoaminergic system on these effects. Acute administration of H. gordonii decreased the immobility of mice in the FST without accompanying changes in general activity in the open-field test during acute treatment, suggesting an antidepressant-like effect. The anti-immobility effect of H. gordonii was prevented by pretreatment of mice with PCPA [an inhibitor of serotonin (5-HT) synthesis], NAN-190 (a 5-HT1A antagonist), ritanserin (a 5-HT2A/2C antagonist), ondansetron (a 5-HT3A antagonist), prazosin (an α1-adrenoceptor antagonist), SCH23390 (a D1 receptor antagonist), yohimbine (an α2-adrenoceptor antagonist), and sulpiride (a D2 receptor antagonist). A significant increase in 5-HT levels in the striatum was detected after acute administration, while 5-HT, norepinephrine and dopamine were significantly elevated after chronic treatment. Results indicated that H. gordonii possesses antidepressant-like activity in the FST by altering the dopaminergic, serotonergic, and noradrenergic systems.

Spectrum-Effect Relationship of Ethyl acetate Fraction in Ethanol Extract fromXiaoyaosan(XYE-E) for Antidepressant Effect Based on1H-NMR / 世界科学技术-中医药现代化

Thearticle is aimed to find the correlation between bioactive components of XYE-E and the antidepressant efficacy, by analyzing the immovability time in tail suspension test (TST) and forced swimming test (FST). Using the method of gray relational analysis, correlation analysis and regression analysis, relating the peak area of each common peak of1H-NMR spectra with the immovability time in TST or FST, we found that there were total 14 chemical components identified in the1H-NMR spectrum of XYE-E. Among them, 8 compounds, including saikosaponin a, saikosaponin c, saikosaponin E, saikosaponin F, saikosaponin G, saikosaponin b2, atractylenolide I and atractylenolide II, had significant correlation with antidepressant efficacy.

Effect of Saraswatarishta in animal models of behavior despair.

Background: Saraswatarishta (SA) is a herbo-mineral formulation consisting of 18 plants some of which are Medhyarasayanas. It has been claimed to be useful in treating central nervous system disorders. Objective: To evaluate antidepressant effect of ‘Saraswatarishta’(SA) alone and in combination with imipramine and fluoxetine in animal models of depression. Materials and Methods: After obtaining IAEC permission, 144 rats (n = 36/part) were randomized into 6 groups‑ Group 1: Distilled water (1 mL), Group 2: Imipramine (30 mg/kg), Group 3: Fluoxetine (10 mg/kg), Group 4: SA (1.8 mL/kg), Group 5: Imipramine + SA, Group 6: Fluoxetine + SA. Effects of study drugs were evaluated in forced swim test (FST) with single exposure to FST (Part 1) and repeated exposure for 14 days (Part 2). In Part 3, reserpine was used with FST and effects of study drugs were evaluated against single exposure to FST. Same model was used with repeated exposures to FST (Part 4). In each part, rats were subjected to open field test (OFT) for 5 min prior to final FST. The variables measured: Immobility time in FST; line crossing, rearing and defecation in the OFT. Results: In all four parts, individual drugs and combinations thereof produced significant decrease in immobility time as compared to control, and extent of decrease was comparable amongst these groups. However, values for combination of fluoxetine with SA group were found to be lesser than that for individual agents in Parts 2 and 3. Combination of SA with imipramine did not enhance its anti‑depressant effect in any of the parts. OFT findings did not vary significantly amongst the study groups. Conclusion: Decreased immobility in FST and absence of generalized stimulation or depression of motor activity in OFT point towards potential antidepressant effect of Saraswatarishta. Its co‑administration with fluoxetine showed more promising effects.