Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test

Considerable attention has been paid to a possible role of immunological dysregulation in the pathogenesis of depression. It has been reported that combined administration of antidepressant drugs and the non-competitive NMDA receptor antagonist amantadine reduces immobility time in the forced swimming test (FST). Moreover, preliminary clinical data show that such a combination of drugs has a beneficial effect on treatment-resistant depressed patients. Since immune activation and a pro-inflammatory response are clearly evident in treatment-resistant depression, the aim of the present study was to examine the effect of a combination of the anti-depressant fluoxetine and amantadine on immunoendocrine parameters in rats subjected to the forced swimming test. The obtained results revealed synergistic antidepressant effects of the combined administration of fluoxetine (10 mg/kg) and amantadine (10 mg/kg) – drugs otherwise ineffective when given separately in the above doses. Antidepressant activity was accompanied with a significant decrease in the capacity of splenocytes to proliferate in response to concanavalin A. Moerover, fluoxetine and the combination of amantadine and fluoxetine reduced relative spleen weight in rats subjected to the FST, compared to rats treated with the vehicle. The combination of amantadine and fluoxetine enhanced the production of the negative immunoregulator interleukin-10 (but not interferon-γ) in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with fluoxetine and amantadine. In summary, the antidepressive efficacy of a combination of fluoxetine and amantadine given in suboptimal doses may be related to the negative immunoendocrine effects of these drugs.     

Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression

The paper describes the effect of amantadine addition to imipramine therapy in patients suffering from treatment-resistant unipolar depression who fulfilled DSM IV criteria for major (unipolar) depression. Fifty patients were enrolled in the study on the basis of their histories of illness and therapy. After a 2-week drug-free period, 25 subjects belonging to the first group were treated only with imipramine twice daily (100 mg/day) for 12 weeks, and 25 subjects belonging to the second group were treated with imipramine twice daily (100 mg/day) for 6 weeks and then amantadine was introduced (150 mg/day, twice daily) and administered jointly with imipramine for the successive 6 weeks. Hamilton Depression Rating Scale (HDRS) was used to assess the efficacy of antidepressant therapy. Imipramine did not change the HDRS score after 3, 6 or 12 weeks of treatment when compared with the washout (before treatment). The addition of amantadine to the classic antidepressant reduced HDRS scores after 6-week joint treatment. Moreover, the obtained pharmacokinetic data indicated that amantadine did not significantly influence the plasma concentration of imipramine and its metabolite desipramine in patients treated jointly with imipramine and amantadine, which suggests lack of a pharmacokinetic interaction. The obtained results indicate that joint therapy with an antidepressant and amantadine may be effective in treatment-resistant unipolar depression.     

Inhibitory effects of amantadine on the production of pro-inflammatory cytokines by stimulated in vitro human blood

Treatment with amantadine (AMA), an N-methyl-D-aspartate (NMDA) receptor antagonist and antidepressant drug, increased the antidepressant activity of subsequent drugs in experimental studies and in patients suffering from treatment-resistant depression (TRD). Recent evidence indicates that depression may be accompanied by activation of an inflammatory response. These data indicate that pro-inflammatory cytokines may play a role in the etiology of depression, particularly in TRD. The present in vitro study shows the ability of AMA, used at concentrations between 10^?7 to 10^?5 M, to reduce the production of the pro-inflammatory cytokines, specifically interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). In addition, AMA treatment increased the production of the negative immunoregulator, interleukin-10 (IL-10). Furthermore, the combined treatment of AMA with fluoxetine (FLU), but not imipramine (IMI), had a stronger immunomodulatory effect on cytokine production than AMA alone. The above data provide additional rationale for the treatment of patients suffering from depression with a combination of AMA and a selective serotonin reuptake inhibitor.     

Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study

Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.     

Concomitant administration of fluoxetine and amantadine modulates the activity of peritoneal macrophages of rats subjected to a forced swimming test

Recent studies show that administration of a non-competitive NMDA receptor antagonist, amantadine (AMA), potentiates the action of antidepressant drugs. Since antidepressants may modulate functioning of the immune system and activation of a pro-inflammatory response in depressive disorders is frequently reported, the aim of the present study was to examine whether a combined administration of AMA and the antidepressant, fluoxetine (FLU), to rats subsequently subjected to a forced swimming test (FST) modifies the parameters of macrophage activity, directly related to their immunomodulatory functions, i.e., arginase (ARG) activity and synthesis of nitric oxide (NO). We found that 10 mg/kg AMA and 10 mg/kg FLU, ineffective in FST for antidepressant-like activity when administered alone, increased the ARG/NO ratio in macrophages when administered concomitantly. This effect was accompanied by a decrease of cellular adherence. Concurrently, the basal metabolic activity of the cells measured with reduction of resazurin, and intracellular host defense as assessed by a synthesis of superoxide anion, were not affected by such antidepressive treatment. Our data indicate that co-administration of AMAand FLU decreases the pro-inflammatory properties of macrophages and causes a redirection of immune response toward anti-inflammatory activity, as one can anticipate in the case of an effective antidepressive treatment.     

Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test.

The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor NG-nitro-L-arginine (L-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion L-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between L-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.     

Antidepressant-like activity of amisulpride in two animal models of depression

Clinical reports suggest that amisulpride, in addition to its antipsychotic efficacy, may also have antidepressant properties. The present study was designed to evaluate potential antidepressant-like activity of amisulpride in two behavioural procedures: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by subchronic (three injections over a 24 h period) administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. The 5 mg/kg dose of amisulpride was marginally effective and higher doses of 10 and 30 mg/kg were inactive. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). Lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. The magnitude of the effect of active doses of amisulpride in the CMS model was comparable to that of imipramine but its onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed. These results provide further support for clinical observations that amisulpride may possess potent and rapid antidepressant activity.     

The immunoregulatory effects of antidepressants

There is some evidence that major depression is accompanied by activation of the inflammatory-response system (IRS). It has been hypothesized that increased production of proinflammatory cytokines may play a role in the etiology of major depression. If increased production of proinflammatory cytokines is at all involved in the etiology of depression, one would expect antidepressive treatments to have negative immunoregulatory effects. This paper reviews the effects of antidepressants, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), heterocyclic antidepressants (HCAs), serotonin-noradrenaline reuptake inhibitors (SNRIs), lithium, l-5-hydroxytroptophan (L-5-HTP), reversible inhibitors of MAO-A (RIMA) on the production of proinflammatory cytokines, e.g. interferon-gamma (IFNgamma), and negative immunoregulatory cytokines and agents, e.g. interleukin-10 (IL-10). In depressed patients, prolonged treatment with antidepressants and mood stabilizers normalizes signs of activation of the IRS, such as increased serum IL-6 and acute phase protein concentrations. In vitro, it has been shown that various types of antidepressive drugs, including TCAs (imipramine; clomipramine); SSRIs (citalopram, fluoxetine, sertraline); lithium; SNRIs (venlafaxine); HCAs (trazodone); RIMAs (moclobemide) and L-5-HTP significantly suppress the ratio of IFNgamma/IL-10 production by peripheral blood immunocytes. These antidepressant drugs appear to have a common effect on the IRS, i.e. in vitro they increase the production of IL-10 by peripheral blood leukocytes. Thus, the results suggest that antidepressants have negative immunoregulatory effects. It may be speculated that antidepressants exert some of their antidepressant effects through their negative immunoregulatory capacities. Copyright 2001 John Wiley & Sons, Ltd.     

Effects of GABAB receptor ligands in animal tests of depression and anxiety

Preclinical evidence strongly implicates GABA(B) receptors in the pathophysiology of several psychiatric disorders including anxiety and depression. In the present study, we investigated the effects of the selective GABA(B) receptor agonists baclofen and SKF 97541, the GABA(B) receptor positive allosteric modulator CGP7930 and the GABA(B) receptor antagonist SCH 50911 in the modified forced swimming test (FST) and in the elevated zero maze test (EZM), i.e. in animal models predictive of antidepressant and antianxiety activities, respectively. The classical antidepressant imipramine and the anxiolytic diazepam were employed as control drugs in the FST and in the EZM, respectively. In the FST, baclofen (0.25 mg/kg), SKF 97541 (0.01-0.05 mg/kg) or CGP 7930 (1-3 mg/kg) and SCH 50911 (1-3 mg/kg) showed antidepressant-like activity, significantly decreasing immobility time; these effects were not related to changes in locomotor activity. The antidepressant effects produced by the GABA(B) receptor ligands were compared with that of imipramine (30 mg/kg). In the EZM, CGP 7930 (1 mg/kg) and SCH 50911 (1-3 mg/kg) produced anxiolytic-like effects, significantly increasing time spent in the open areas of the maze; those effects were comparable with the effects of diazepam (1-2 mg/kg). Our results indicate that differential manipulation of GABA(B) receptors can modify behaviors relevant to depression and anxiety. The GABA(B) receptor positive allosteric modulator CGP 7930 and the antagonist SCH 50911 show both antidepressant and anxiolytic profile, while the GABA(B) receptor agonists (baclofen and SKF 97541) produce effects that are characteristic of antidepressant drugs.     

Antidepressant effects of apocynum venetum leaves in a forced swimming test.

An extract of the leaves of Apocynum venetum L. (Apocynaceae) markedly shortened the immobility time of male rats in a forced swimming test (FST) in a dose range of 30-125 mg/kg, indicating a possible antidepressant activity. This effect was comparable to that of the tricyclic antidepressant imipramine (20 mg/kg). Neither imipramine (20 mg/kg) nor the Apocynum extract in various doses (30, 60, 125 mg/kg) produced any overt behavioural change or motor dysfunction in the open field test. This result confirms the assumption that the antidepressant effect of an Apocynum extract in the FST is specific. Further, it can be speculated that this effect might be related to hyperoside and isoquercitrin which are major flavonoids in the extract.     

Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio

There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.     

Effect of joint administration of imipramine and amantadine on binding of [3H]7-OH-DPAT to dopamine D3 receptors in peripheral blood lymphocytes of the patients with drug-resistant unipolar depression

Treatment of the patients suffering from therapy-resistant unipolar depression with joint administration of imipramine (twice daily, 100-150 mg/day) and amantadine (twice daily, 150 mg/day) for four to six weeks resulted in the significant increase in the binding of [3H]7-OH-DPAT to dopamine D3 receptors in the peripheral blood lymphocytes. This effect correlated well with the clinical improvement, estimated with Hamilton's Depression Rating Scale. In the light of the above data, it seems justified to postulate that joint therapy with imipramine and amantadine may be successful in the treatment-resistant unipolar depression.     

Evaluation of antidepressant activity of vanillin in mice

Objective:

The main objective of this study was to evaluate antidepressant activity of vanillin in mice models of depression.

Materials and Methods:

Animals were divided into five groups, consisting six mice in each group. Out of these, three groups served as control (distilled water, imipramine,and fluoxetine) and the remaining two groups received test drug in two different doses (10mg/kg and 100mg/kg). All the drugs were administered orally one hour before the test procedure for acute study and daily for ten days for chronic study. Mice were subjected to forced swim (FST) and tail suspension tests (TST).

Results:

Both the doses of vanillin reduced the immobility duration in TST as well as in FST. In TST, there was a statistically significant decrease in the immobility in all the groups when compared to the control (distilled water) group. But the reduction of immobility in FST did not show statistically significant reduction in immobility in the groups treated with vanillin when compared with control. In the chronic study group that received vanillin at a dose of 100mg/kg, the immobility reduction was significantly lower when compared to the group receiving fluoxetine.

Conclusion:

Vanillin at the dosage of 100mg/kg has demonstrated antidepressant activity in mice, which is comparable with fluoxetine.KEY WORDS: Antidepressant, depression, fluoxetine, imipramine, vanillin     

Chronic treatment with imipramine and lithium increases cell proliferation in the hippocampus in adrenocorticotropic hormone-treated rats

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14 d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14 d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.     

The forced swim test has poor accuracy for identifying novel antidepressants

Despite the prevalence of treatment-resistant depression, many pharmaceutical companies have abandoned the development of new antidepressants. Experts have attributed this, in part, to the low quality of preclinical tests available in this field, often citing over-reliance on animal behavioral screens, such as the forced swim test (FST). This retrospective review assessed whether compounds tested in the FST by major pharmaceutical companies were shown to have antidepressant effects in humans. Of 109 compounds identified, only 28% had been explored for antidepressant effects in humans. Of these, there were only three for which the FST appeared to positively predict antidepressant efficacy, but none are currently approved to treat any type of depression. With such poor accuracy for identifying novel antidepressants, the FST might not be a useful screening tool for this purpose.     

Additive effects of lithium and antidepressants in the forced swimming test: further evidence for involvement of the serotoninergic system

In the mouse forced swimming test (FST) pretreatment with a subactive dose of lithium (1 mEq/kg), given IP 45 min before the test, facilitated the antidepressant activity of iprindole, fluoxetine, and moclobemide (given IP 30 min before the test). These antidepressants (ADS) were not active alone in the FST in this study. Moreover, when subactive lithium was combined with a wide range of ADS, each given at subactive doses, those ADS with serotoninergic properties (e.g. imipramine, citalopram, paroxetine, fluoxetine, trazodone, mianserin, and moclobemide) significantly reduced immobility times. ADS acting primarily on noradrenaline (NA) or dopamine (DA) systems (desipramine, maprotiline, viloxazine, and bupropion) did not significantly decrease immobility when given in combination with lithium. This was also the case for RO 16 6491 [a reversible, B specific monoamine oxidase inhibitor (MAOI)], nialamide, and pargyline (both irreversible, mixed MAOIs). The anti-immobility effect of iprindole in combination with lithium suggests either a direct or indirect action on the serotonin (5HT) system by this ADS whose mechanism of action remains obscure. These results, using an animal behavioral model of depression and combining our present knowledge of the acute action of various ADS, support the hypothesis that the potentiation by lithium of ADS is via direct 5HT mechanisms,indirectly via a NA/5HT link, and/or by second messenger systems. Lithium may also facilitate the expression of antidepressant activity of ADS not active by themselves in the FST.     

Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus

BACKGROUND AND PURPOSE Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients of Panax ginseng with little toxicity and has been shown to have neuroprotective effects. In this study, we investigated the antidepressant-like effect of Rg1 in models of depression in mice. EXPERIMENTAL APPROACH The effects of Rg1 were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Rg1 was also investigated in the chronic mild stress (CMS) mouse model of depression with imipramine as the positive control. Changes in hippocampal neurogenesis and spine density, the brain-derived neurotrophic factor (BDNF) signalling pathway, and serum corticosterone level after chronic stress and Rg1 treatment were then investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressive mechanisms of Rg1. KEY RESULTS Ginsenoside Rg1 exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. It was also effective in the CMS model of depression. Furthermore, Rg1 up-regulated the BDNF signalling pathway in the hippocampus and down-regulated serum corticosterone level during the CMS procedure. In addition, Rg1 was able to reverse the decrease in dendritic spine density and hippocampal neurogenesis caused by CMS. However, Rg1 had no discernable effect on the monoaminergic system. CONCLUSIONS AND IMPLICATIONS Our results provide the first evidence that Rg1 has antidepressant activity via activation of the BDNF signalling pathway and up-regulation of hippocampal neurogenesis.