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.

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.

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.

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.

Ketamine alters behavior and decreases BDNF levels in the rat brain as a function of time after drug administration

Objective: To evaluate behavioral changes and brain-derived neurotrophic factor (BDNF) levels in rats subjected to ketamine administration (25 mg/kg) for 7 days. Method: Behavioral evaluation was undertaken at 1 and 6 hours after the last injection. Results: We observed hyperlocomotion 1 hour after the last injection and a decrease in locomotion after 6 hours. Immobility time was decreased and climbing time was increased 6 hours after the last injection. BDNF levels were decreased in the prefrontal cortex and amygdala when rats were killed 6 hours after the last injection, compared to the saline group and to rats killed 1 hour after the last injection. BDNF levels in the striatum were decreased in rats killed 6 hours after the last ketamine injection, and BDNF levels in the hippocampus were decreased in the groups that were killed 1 and 6 hours after the last injection. Conclusion: These results suggest that the effects of ketamine on behavior and BDNF levels are related to the time at which they were evaluated after administration of the drug. .

Anti-fatigue effects of polysaccharides extracted from Rhodiolae Radix.

The purpose of the present study was to determine the effects of polysaccharide from Rhodiolae Radix (PRR) on physical fatigue using a forced swimming test in male mice. 96 mice were divided randomly into four groups based on body weight (n = 24). One of the groups was the control group; the others were PRR supplemented groups (25, 50 and 100 mg/kg body weight). Forced swimming test of mice were carried out after 28 days of PRR administration, and the blood lactic acid (BLA), blood urea nitrogen (BUN), liver glycogen and muscle glycogen contents were deter-mined. The data suggest that PRR can extend the exhaustive swimming time of the mice, as well as increase the tissue glycogen contents, and decrease the BLA and BUN contents. These results indicated that PRR had significant anti-fatigue effects.

Anti-fatigue effects of polysaccharides extracted from Rhodiolae Radix.

The purpose of the present study was to determine the effects of polysaccharide from Rhodiolae Radix (PRR) on physical fatigue using a forced swimming test in male mice. 96 mice were divided randomly into four groups based on body weight (n = 24). One of the groups was the control group; the others were PRR supplemented groups (25, 50 and 100 mg/kg body weight). Forced swimming test of mice were carried out after 28 days of PRR administration, and the blood lactic acid (BLA), blood urea nitrogen (BUN), liver glycogen and muscle glycogen contents were deter-mined. The data suggest that PRR can extend the exhaustive swimming time of the mice, as well as increase the tissue glycogen contents, and decrease the BLA and BUN contents. These results indicated that PRR had significant anti-fatigue effects.

Preliminary Study: Effects of Social Instability Stress on Depressive Behaviours in Ovariectomised Rats

Background: Depression is one of the common post-menopausal symptoms. In addition to estrogen deficiency, social instability stress may contribute as an additional underlying factor in the development of depressive behaviour in females. Therefore, this study was aimed at examining the influence of social instability stress on depressive behaviour in ovariectomized rats. Methods: The rats were divided into four groups (n = 5 per group); (i) sham-operated control without stress, (ii) sham-operated control with stress, (iii) ovariectomized without stress, and (iv) ovariectomized with stress. These rats were subjected to social instability stress procedures for 15 days prior to an enforced swimming test. Struggling, immobility, and swimming times were recorded promptly. Results: The results were analysed using the one-way analysis of variance (ANOVA) and a P value of < 0.05 was considered as significant. The mean durations of struggling, immobility, and swimming behaviour were significantly distinct among the four groups. Ovariectomized rats exhibited a substantial decrease in struggling and swimming behaviour, and an increase in immobility behaviour in comparison with the sham-operated controls (P < 0.05). Ovariectomized rats with stress displayed a supplementary decrease in struggling and swimming behaviour as well as an advanced increase in immobility behaviour, compared to sham-operated controls with or without stress (P < 0.05). Conclusion: In summary, these findings suggest that ovariectomized rats encountered an augmented amount of depressive behaviour following social instability stress.

Walnut extract exhibits anti-fatigue action via improvement of exercise tolerance in mice / 한국실험동물학회지

This study was conducted to investigate the anti-fatigue effect of walnut extract (WE) on forced swimming capacity in mice. Twenty-eight male ICR mice were randomly divided into four groups, a vehicle control (VC) or one of three WE administered groups (300, 600 and 900 mg/kg/day). WE was orally administered to mice once a day for 4 weeks, during which time a forced swimming test was conducted once a week. The vehicle control group was given a corresponding volume of sterile distilled water. After 4 weeks, the forced swimming capacity and levels of blood lactate, glucose, glutamine, ammonia and triacylglycerol, and liver glycogen were measured. In the WE administration group (600 and 900 mg/kg) the maximum swimming time increased significantly when compared with the vehicle control group. WE (600 and 900 mg/kg) significantly decreased the levels of lactate andammonia and increased the blood glutamine levels and liver glycogen content after forced swimming relative to the vehicle control group. The results of this study demonstrated the anti-fatigue effects of WE in a dose-dependent manner. The effects of WE at 600 and 900 mg/kg were similar. Overall, these results suggest that walnut has anti-fatigue activity and could elevate exercise tolerance.

Changes in c-Fos Expression in the Forced Swimming Test: Common and Distinct Modulation in Rat Brain by Desipramine and Citalopram

Rodents exposed to a 15-min pretest swim in the forced swimming test (FST) exhibit prolonged immobility in a subsequent 5-min test swim, and antidepressant treatment before the test swim reduces immobility. At present, neuronal circuits recruited by antidepressant before the test swim remain unclear, and also less is known about whether antidepressants with different mechanisms of action could influence neural circuits differentially. To reveal the neural circuits associated with antidepressant effect in the FST, we injected desipramine or citalopram 0.5 h, 19 h, and 23 h after the pretest swim and observed changes in c-Fos expression in rats before the test swim, namely 24 h after the pretest swim. Desipramine treatment alone in the absence of pretest swim was without effect, whereas citalopram treatment alone significantly increased the number of c-Fos-like immunoreactive cells in the central nucleus of the amygdala and bed nucleus of the stria terminalis, where this pattern of increase appears to be maintained after the pretest swim. Both desipramine and citalopram treatment after the pretest swim significantly increased the number of c-Fos-like immunoreactive cells in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim. These results suggest that citalopram may affect c-Fos expression in the central nucleus of the amygdala and bed nucleus of the stria terminalis distinctively and raise the possibility that upregulation of c-Fos in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim may be one of the probable common mechanisms underlying antidepressant effect in the FST.

Participación de las hormonas gonadales en el efecto de los fármacos antidepresivos en la rata macho / Participation of gonadal hormones in the effect of antidepressant drugs in male rats

It has been proposed that gonadal hormones participate in regulation of mood and emotion in men as well as in the effect of psychoactive drugs, such as antidepressants. However, evaluation of this type of interactions has been poorly studied in clinic and basic studies. The objective of the present study was to determine the role of gonadal hormones, testosterone (T) and 17β-estradiol (E2), one of its main metabolites, in the effect of two antidepressant drugs: desipramine and fluoxetine. The former is a tricyclic antidepressant that inhibits noradrenaline reuptake in a preferential manner, while the second is a serotonin selective reup-take inhibitor (SSRI) and the most prescribed antidepressant. Behavioral evaluations were conducted in adult male rats, intact or orchidectomized (Orx), treated with T (0-2 mg/rata), E2 (0-40 µg/rata), desipramine (0-20 mg/kg), fluoxetine (0-20 mg/kg) and their combinations. Forced swimming test was used as an animal model to detect antidepressant-like effect induced by treatments, on the basis of its predictive validity. We found that desipramine and fluoxetine produced an anti-depressant-like effect in gonadally intact male rats. However, the antidepressant-like effect of both treatments was cancelled in Orx males. Treatment with E2, but not with T, produced antidepressant-like actions in Orx males. Interestingly, treatment with E2 restored the antidepressant-like effect of desipramine and fluoxetine, while supplementation with T only reestablished the antidepressant-like action of desipramine, evidencing that gonadal hormones have a differential participation in regulation of neurotransmitter systems involving in the antidepressant effect. In conclusion, the main testicular androgen T, participates in the expression of the effect of antidepressant drugs, mainly via conversion to its estrogenic metabolite E2. These results give support to the idea that a combined therapy of gonadal hormones and antidepressant drugs may be more convenient to treat depressive disorders in hypogonadal men resistant to conventional antidepressant drugs.

Se ha propuesto que las hormonas gonadales participan en la regulación del estado de ánimo en los varones, y en el efecto de los fármacos psicoactivos, tales como los antidepresivos. Sin embargo, la evaluación de este tipo de interacciones ha sido estudiada escasamente. El objetivo del presente trabajo fue determinar el papel que cumplen las hormonas testosterona (T) y 17β-estradiol (E2), uno de sus principales metabolitos, en el efecto de dos fármacos antidepresivos utilizados en la práctica clínica, desipramina y fluoxetina. El primero es un tricíclico con acciones sobre el sistema noradrenérgico, mientras que la fluoxetina es un inhibidor selectivo de la recaptura de serotonina. Las evaluaciones se llevaron a cabo utilizando ratas macho adultas jóvenes, gonadalmente intactas u orquidectomizadas (Orx), bajo tratamiento con T (0-1 mg/rata), E2 (0-40 µg/rata), desipramina (0-20 mg/kg), fluoxetina (0-20 mg/kg) y sus respectivas combinaciones. Se utilizó la prueba de nado forzado (PNF) para detectar las acciones antidepresivas de los tratamientos. Encontramos que desipramina y fluoxetina redujeron la conducta de depresión en los machos gonadalmente intactos; sin embargo, el efecto de ambos tratamientos fue abolido por la orquidectomía. El tratamiento de restitución hormonal con E2, pero no con T, indujo acciones antidepresivas en los machos Orx. A su vez, cuando los animales Orx recibieron la restitución con T se produjo la recuperación del efecto antidepresivo de la desipramina, mientras que el E2 restableció las acciones antidepresivas de ambos fármacos. En conclusión, el principal andrógeno de origen testicular, la T, participa en la expresión del efecto de los fármacos antidepresivos explorados en el presente estudio, principalmente a través de su metabolito estrogénico, el E2. Estos resultados apoyan la idea de que una terapia adjunta de tratamientos hormonales y antidepresivos sería de beneficio para varones hipogonadales que cursen con depresión resistente a los fármacos antidepresivos convencionales.