Reduction In Immobility Period Research Articles

Prophylactic administration of rosmarinic acid ameliorates depression-associated cardiac abnormalities in Wistar rats: Evidence of serotonergic, oxidative, and inflammatory pathways.

Psychiatric disorders and associated cardiac comorbidities have increased the risk of mortality worldwide. Researchers reported that depression increases the possibility of future cardiac abnormalities by approximately 30%. Therefore, there is an unmet need to develop therapeutic interventions to treat depression and associated cardiac abnormalities. The present study was conducted to evaluate the prophylactic effect of rosmarinic acid (RA) against chronic unpredictable stress (CUS)-induced depression associated cardiac abnormalities in Wistar rats. The CUS paradigm, which comprised several stressors, was employed for 40 days to induce depressive-like behavior and associated cardiac abnormalities in rats. Along with CUS, RA at a dose of 25 and 50 mg/kg was administered orally to two groups of animals for 40 days. Behavioral tests (forced swim test and sucrose consumption test) and molecular biomarkers (corticosterone and serotonin) were performed. Electrocardiography was performed before CUS (Day 0), Day 20, and Day 40 to study electrocardiogram parameters. Furthermore, changes in body weight, organ weight, tissue lipid peroxidation, glutathione, catalase, cTn-I, MMP-2, and proinflammatory cytokines (TNF-α and IL-6) were estimated. Our results showed that RA treatment caused a reduction in immobility period, adrenal hyperplasia, corticosterone level, tissue lipid peroxidation, cTn-I, MMP-2, proinflammatory cytokines, and QRS complex duration, while an increase in sucrose consumption, brain serotonin level, T-wave width, glutathione, and catalase activity as compared with the CUS-control group. The results of our study proved that RA administration ameliorates CUS-induced depression-associated cardiac abnormalities in rats via serotonergic, oxidative, and inflammatory pathways.

Preclinical evaluation of the impact of cilostazol on anti-depressant activity of fluoxetine

The current anti-depressant agents have limitations like the slow onset of action, moderate efficacy, withdrawal symptoms, incompliance of treatment, and instabilities in circadian rhythm. Their therapeutic use is quite restricted and produces inadequate or partial symptomatic relief of depression which may lead to treatment- resistance depression. In the view of a new strategy, second messengers (cAMP, cGMP) and their signalling pathways are emerging as novel targets for anti-depressants. The present study conducted to evaluate the augmentation property of cilostazol on the anti-depressant activity of fluoxetine. Traditional anti-depressant models like forced swimming test and tail suspension test were employed. Mice were randomly grouped into six groups, with six rats in each. Each group was treated, as mentioned in the study. The reduction in immobility period of each mouse was noted. These results were analysed by ordinary one way ANOVA followed by Tukey’s multiple comparison test. Cilostazol at a dose of 20 mg/kg i.p significantly reduced immobility period when compared to cilostazol 10 mg/kg i.p and normal saline. Cilostazol 10 mg/kg i.p also decreased immobility period significantly when compared to normal saline by forced swimming test. Fluoxetine 20 mg/kg i.p + cilostazol 20 mg/kg i.p produced a highly significant reduction in the immobility period in comparison with all groups except with fluoxetine 20 mg/kg i.p + cilostazol 10 mg/kg i.p in forced swimming test. This study concludes that cilostazol has produced dose-dependent anti-depressant activity. This study also emphasises cilostazol can augment the anti-depressant activity of fluoxetine.

EFFECT OF FLAVONE AND ITS MONOHYDROXY DERIVATIVES ON ANIMAL MODELS OF DEPRESSION IN SWISS ALBINO MICE

Objectives: This research was designed to investigate the antidepressant activity of a few structurally related flavones (flavone, 3‑hydroxyflavone, and 7‑hydroxyflavone) and the possible mechanisms involved.
 Methods: Antidepressant activity was evaluated in mice by subjecting them to forced swim test and tail suspension test. The involvement of adrenergic, serotonergic, nitric oxide (NO), and opioid mechanisms was investigated using suitable interacting chemicals.
 Results: Flavone, 3‑hydroxyflavone, and 7‑hydroxyflavone exhibited a significant and dose‑dependent reduction in total time of immobility in the forced swim test and tail suspension test. Pre‑treatment with alpha‑methyl‑para‑tyrosine and parachlorophenyl alanine attenuated the reduction in immobility period produced by flavone and its derivatives in forced swim test. Naloxone pre‑treatment partially reversed the effect of flavone while L‑arginine pre‑treatment did not alter their effect.
 Conclusion: The investigated flavones exhibited promising antidepressant activity in both the animal models of depression. However, the flavone compounds did not alter the motor coordination and ambulatory behavior in the Rotarod and locomotor activity test. The participation of serotonergic, adrenergic, and opioid mechanism in the antidepressant activity of these compounds was elucidated from the results, and the role of NO pathway was excluded.

A comparative study of the antidepressant effect of ondansetron and granisetron on Albino mice

Background: Ondansetron and granisetron are selective 5-HT receptor antagonists used as antiemetics. The present study as aimed at comparing the antidepressant activity of ondansetron and granisetron in animal experimental models.Methods: The study was done after obtaining approval from the institutional animal ethical committee of JJM Medical college, Davangere and CPCSEA. A total of 24 mice of either sex and of weight between 20-40g were included in the study. The antidepressant activity of ondansetron and granisetron was evaluated in mice using forced swim test model (FST) and tail suspension test model (TST). In both the experimental models animals were divided into 4 groups and received the following drugs- Group 1 (control) - normal saline 10mg/kg i.p, Group 2 (standard)-fluoxetine 10mg/kg i.p, Group 3(test drug 1), ondansetron 2mg/kg i.p, Group 4 (test drug 2)- granisetron 0.5mg/kg i.p. The duration of immobility was noted and compared amongst the 4 groups in both the models 60 min after drug administration. The observations were analysed using ANOVA (one way) and post hoc Tukey’s test.Results: The test drugs showed significant reduction in duration of immobility in both the models. In FST and TST models, granisetron (0.5mg/kg i.p) showed a significant reduction in immobility period of 10.33 sec and 67 secs respectively when compared to ondansetron (2mg/kg i.p) and the standard drug fluoxetine (10mg/kg i.p).Conclusions: The results of study suggest that granisetron may be useful as a potential candidate for treatment of depression. Hence further animal studies with different model for depression and clinical studies should be conducted in order to choose the better drug for treatment PONV which is often associated with depression.

Evaluation of antidepressant activity of tramadol in mice: an experimental study

Background: In spite of availability of effective antidepressant drugs, depression continues to be a major problem. Hence, great interest is being taken in development of innovative antidepressants. Tramadol (TRM) is a centrally acting opioid agonist, which is clinically effective in the treatment of moderate to severe pain. By virtue of its action of inhibiting norepinephrine and serotonin uptake, it can function as an antidepressant like venlafaxine. Hence, this study was planned to evaluate antidepressant activity of TRM in comparison and in combination with fluoxetine (FLX) in albino mice. Methods: TRM (20 and 40 mg) and FLX (20 mg) were administered i.p., alone and in combination once daily for acute (7 days) and chronic (14 days) period to Swiss albino mice of either sex. The immobility period of control and treated mice was recorded in forced swimming test (FST) and tail suspension test (TST). The open field test was also done for same period to test the locomotor activity in animal. The antidepressant effect of TRM was compared with FLX and normal saline treated group for acute and chronic study period. Results: TRM (20 and 40 mg) treated group produced significant antidepressant effect alone and in combination with FLX (20 and 40 mg) as indicated by reduction in immobility period compared with control group in FST and TST. TRM and FLX treated groups did not show significant activity in open field test when compared with control group. Conclusions: This study shows TRM has antidepressant activity in standard models of depression.

Comparative efficacy of behavioral despair models in depicting antidepressant-like effect of tramadol

Background: Experimental evaluation of antidepressants (ADs) in diverse animal models is the need of time. There is a constant search for newer models with ease and rapid screening of AD activity. As earlier studies highlight AD effect of tramadol in animal models, the study was undertaken to compare antidepressant-like effect of tramadol in two models of behavioural despair in mice. Methods: Tramadol was administered intraperitoneally (i.p.) at two different doses of 20 and 40 mg/kg, once daily for 7 days to Swiss albino mice. The immobility period of control and drug-treated mice was recorded in tail suspension test (TST) and forced swim test (FST). The antidepressant (AD) effect of tramadol was compared with control (NS) and reference drug imipramine (10 mg/kg, p.o.), administered orally (p.o.) for seven successive days. Results: Tramadol in tail suspension test (TST) produced significant antidepressant effect at 20 and 40 mg/kg doses, as depicted by reduction in immobility period of drug-treated mice compared to control group. The efficacy of tramadol at dose of 40 mg/kg was comparable to that of imipramine treated group (p 0.05). Conclusion : The results of the present study depict antidepressant-like activity of tramadol in both the models of depression TST and FST. But TST in mice seems to be more efficacious in appraising the antidepressant like effect of tramadol.

Possible involvement of sigma‐1 receptors in the anti‐immobility action of bupropion, a dopamine reuptake inhibitor

Sigma receptors particularly, sigma-1 subtype is known to modulate the release of catecholamines in the brain and may participate in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the anti-immobility-like effect of bupropion (a dopamine reuptake inhibitor) using the forced swim test (FST) in mice. Bupropion produced dose-dependent (10-40 mg/kg, i.p.) reduction in immobility period and the ED(50) value was found to be 18.5 (7.34-46.6) mg/kg, i.p. (+)-Pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergistic response when it was co-administered with a subeffective dose of bupropion (10 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of bupropion (20 mg/kg, i.p.). The various modulators used in the study did not show any effect per se on locomotor activity except bupropion which at a higher dose (15-40 mg/kg, i.p.) significantly increased the locomotor activity. The results for the first time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion.

Venlafaxine reverses chronic fatigue-induced behavioral, biochemical and neurochemical alterations in mice

A state of chronic fatigue was produced in mice by subjecting them to forced swim inside a rectangular jar of specific dimensions everyday for a 6 min session for 15 days. Immobility period was recorded on alternate days. The effect of venlafaxine, a dual reuptake inhibitor of serotonin and norepinephrine was evaluated in this murine model of chronic fatigue. Venlafaxine was administered daily and on the days of testing, it was injected 30 min before forced swim session. On the 16th day i.e. 24 h after the last dose of venlafaxine, various behavioral, biochemical and neurotransmitter estimations in the brain were carried out. There was a significant increase in immobility period in vehicle treated mice on successive days, the maximum immobility score reaching on the 7th day and sustained till 15th day. Behavioral parameters revealed hyperlocomotion, anxiety response, muscle incoordination, hyperalgesia and memory deficit. Biochemical analysis showed a significant increase in lipid peroxidation, nitrite and myeloperoxidase levels and a decrease in the reduced glutathione (GSH) levels in brain homogenates. Further, there was a decrease in adrenal ascorbic acid following chronic forced swim. The neurotransmitter estimations in the brain samples revealed a decrease in norepinephrine, serotonin and dopamine levels on chronic exposure to forced swim for 15 days. Daily treatment with venlafaxine (8 and 16 mg/kg, i.p.) for 15 days produced a significant reduction in immobility period and reversed various behavioral, biochemical and neurotransmitter alterations induced by chronic fatigue. Venlafaxine could be of therapeutic potential in the treatment of chronic fatigue.

Possible involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant activity of berberine chloride

Berberine is an isoquinoline alkaloid isolated from Berberis aristata, a major herb widely used in Indian and Chinese systems of medicine. Berberine possessed a wide range of biological activity including antidiarrheal, antimicrobial, anti-inflammatory effects and some central nervous system activity as well. The present study was designed to explore the antidepressant activity and its possible mechanism of action. Further, the involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of berberine chloride was investigated. The antidepressant activity was assessed in forced-swim and tail-suspension tests. Total immobility period was recorded during a six-min test. Berberine (5-20 mg/kg, i.p.) produced a reduction in immobility period in both the tests. When berberine (5 mg/kg, i.p.) was co-administered with other antidepressant drugs, it enhanced the anti-immobility effect of subeffective doses of imipramine (2 mg/kg, i.p.), desipramine (5 mg/kg, i.p.), tranylcypromine (4 mg/kg, i.p.), fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) in forced-swim test. However, berberine did not modify the effects of mianserine (32 mg/kg, i.p.) or trazodone (2 mg/kg, i.p.), the two atypical antidepressant drugs. The neurochemical analysis revealed that berberine (5 mg/kg, i.p.) increased the levels of norepinephrine, serotonin or dopamine in the mouse whole brain. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced-swim test was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of berberine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of berberine (2 mg/kg, i.p.) in the forced-swim test. Furthermore, the reduction in the immobility period elicited by berberine (5 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators and their combination with berberine did not produce any changes in locomotor activity. Our findings demonstrated that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine) and further, the antidepressant-like effect of berberine in the forced-swim test involved an interaction with the l-arginine-NO-cGMP pathway.

Involvement of sigma-1 receptor modulation in the antidepressant action of venlafaxine

Multiple lines of investigation have explored the role of sigma receptors in mental depression. Sigma receptors particularly, sigma-1 subtype is known to modulate the release of various catecholamines in the brain and may play, in some way, a role in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the antidepressant-like effect of venlafaxine (dual serotonin and norepinephrine reuptake inhibitor) in the mouse forced swim test (FST). Immobility period in the forced swim test was registered for a total period of 6 min. Venlafaxine produced dose-dependent (4-16 mg/kg, i.p.) reduction in immobility period. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergism with subeffective dose of venlafaxine (2 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of venlafaxine (8 mg/kg i.p.). The various modulators used in the study did not produce any changes in locomotor activity per se except venlafaxine which at higher dose (16 mg/kg, i.p.) significantly increased the locomotor activity in mice. The results for the first time demonstrated that the anti-immobility effects of venlafaxine in the FST possibly involve an interaction with sigma-1 receptors.

Involvement of l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of venlafaxine in mice

The involvement of l-arginine–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of venlafaxine (dual serotonin and norepinephrine reuptake inhibitor) was investigated in mice. The antidepressant activity was assessed in forced swim test (FST) behavioral paradigm. Total immobility time was registered during the period of 6 min. Venlafaxine produced dose-dependent (4–16 mg/kg, i.p.) reduction in immobility period. The antidepressant-like effect of venlafaxine (8 mg/kg, i.p.) was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of venlafaxine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of venlafaxine (2 mg/kg, i.p.) in the FST. Furthermore, the reduction in the immobility time elicited by venlafaxine (8 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators used in the study did not produce any changes in locomotor activity per se. The results demonstrated that the antidepressant-like effect of venlafaxine in the FST involved an interaction with the l-arginine–NO–cGMP pathway.

Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear; however, a number of studies have shown that oxidative stress may be involved in its pathogenesis. In the present study, a mouse model of CFS was used in which mice were forced to swim for one 6-minute session on each day for 15 days and the immobility period was recorded. There was a significant increase in immobility period in saline-treated mice on successive days. Intraperitoneal treatment with the potent antioxidants carvedilol (5 mg/kg) and melatonin (5 mg/kg) produced a significant reduction in immobility period. Similar results were observed with herbal preparations administered orally: Withania somnifera (100 mg/kg), quercetin (50 mg/kg), and St. John's wort (Hypericum perforatum L., 10 mg/kg). Biochemical analysis revealed that chronic swimming significantly induced lipid peroxidation and decreased glutathione (GSH) levels in the brains of mice. The rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Co-administration of antioxidants carvedilol, melatonin, W. somnifera, quercetin or St. John's wort significantly reduced lipid peroxidation and restored the GSH levels decreased by chronic swimming in mice. Further, the treatment increased levels of SOD in the forebrain and of catalase. The findings strongly suggest that oxidative stress plays a significant role in the pathophysiology of CFS and that antioxidants could be useful in the treatment of CFS.

Experimental assessment of topical liposomal cyclosporin

Berberine is an isoquinoline alkaloid isolated from Berberis aristata, a major herb widely used in Indian and Chinese systems of medicine. Berberine possessed a wide range of biological activity including antidiarrheal, antimicrobial, anti-inflammatory effects and some central nervous system activity as well. The present study was designed to explore the antidepressant activity and its possible mechanism of action. Further, the involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of berberine chloride was investigated. The antidepressant activity was assessed in forced-swim and tail-suspension tests. Total immobility period was recorded during a six-min test. Berberine (5-20 mg/kg, i.p.) produced a reduction in immobility period in both the tests. When berberine (5 mg/kg, i.p.) was co-administered with other antidepressant drugs, it enhanced the anti-immobility effect of subeffective doses of imipramine (2 mg/kg, i.p.), desipramine (5 mg/kg, i.p.), tranylcypromine (4 mg/kg, i.p.), fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) in forced-swim test. However, berberine did not modify the effects of mianserine (32 mg/kg, i.p.) or trazodone (2 mg/kg, i.p.), the two atypical antidepressant drugs. The neurochemical analysis revealed that berberine (5 mg/kg, i.p.) increased the levels of norepinephrine, serotonin or dopamine in the mouse whole brain. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced-swim test was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of berberine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of berberine (2 mg/kg, i.p.) in the forced-swim test. Furthermore, the reduction in the immobility period elicited by berberine (5 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators and their combination with berberine did not produce any changes in locomotor activity. Our findings demonstrated that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine) and further, the antidepressant-like effect of berberine in the forced-swim test involved an interaction with the l-arginine-NO-cGMP pathway.