Increase In Duration Of Immobility Research Articles

Impacts of Electroconvulsive Therapy on the Neurometabolic Activity in a Mice Model of Depression: An Ex Vivo 1H-[13C]-NMR Spectroscopy Study

Electroconvulsive therapy (ECT) is an effective treatment for severe and drug-resistant depression, yet its mode of action remains poorly understood. This study aimed to evaluate the effects of ECT on neurometabolism using ex vivo 1H-[13C]-NMR spectroscopy in conjunction with intravenous infusion of [1,6-13C2]glucose in a chronic variable mild stress (CVMS) model of depression. Both CVMS and control mice were subjected to seven sessions of electroconvulsive shock under mild isoflurane anesthesia. The CVMS mice exhibited a reduction in sucrose preference (CVMS 67.1 ± 14.9%, n = 5; CON 86.5 ± 0.6%, n = 5; p = 0.007), and an increase in immobility duration (175.9 ± 22.6 vs. 92.0 ± 23.0 s, p < 0.001) in the forced-swim test. The cerebral metabolic rates of glucose oxidation in glutamatergic (CMRGlc(Glu)) (CVMS 0.134 ± 0.015 µmol/g/min, n = 5; CON 0.201 ± 0.045 µmol/g/min, n = 5; padj = 0.04) and GABAergic neurons (CMRGlc(GABA)) (0.030 ± 0.002 vs. 0.046 ± 0.011 µmol/g/min, padj = 0.04) were reduced in the prefrontal cortex (PFC) of CVMS mice. ECT treatment in CVMS mice normalized sucrose preference [F(1,27) = 0.0024, p = 0.961] and immobility duration [F(1,28) = 0.434, p = 0.515], but not the time spent in the center zone (CVMS + ECT 10.4 ± 5.5 s, CON + sham 22.3 ± 11.4 s, padj = 0.0006) in the open field test. The ECT-treated CVMS mice exhibited reduced (padj = 0.021) CMRGlc(Glu) in PFC (0.169 ± 0.026 µmol/g/min, n = 8) when compared with CVMS mice, which underwent the sham procedure (0.226 ± 0.030 µmol/g/min, n = 8). These observations are consistent with ECT’s anticonvulsant hypothesis for its anti-depressive action.

The α-7 Nicotinic Receptor Positive Allosteric Modulator Alleviates Lipopolysaccharide Induced Depressive-like Behavior by Regulating Microglial Function, Trophic Factor, and Chloride Transporters in Mice.

Neuroinflammation contributes to the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain-derived neurotrophic factor (BDNF), Na-K-Cl cotransporter-1 (NKCC1), and K-Cl cotransporter-2 (KCC2) due to activation of BDNF-tropomyosin receptor kinase B (TrkB) signaling. Allosteric modulation of α7 nAChRs has not been investigated on BDNF, KCC2, and NKCC1 during LPS-induced depressive-like behavior. Therefore, we examined the effects of PNU120596, an α7 nAChR positive allosteric modulator, on the expression of BDNF, KCC2, and NKCC1 in the hippocampus and prefrontal cortex using Western blot analysis, immunofluorescence assay, and real-time polymerase chain reaction. The effects of ANA12, a TrkB receptor antagonist, on LPS-induced cognitive deficit and depressive-like behaviors were determined using the Y-maze, tail suspension test (TST), and forced swim test (FST). Pharmacological interactions between PNU120596 and ANA12 were also examined. Experiments were conducted in male C57BL/6J mice. LPS administration (1 mg/kg) resulted in increased expression of BDNF and the NKCC1/KCC2 ratio and decreased expression of KCC2 in the hippocampus and prefrontal cortex. PNU120596 pretreatment (4 mg/kg) attenuated the LPS-induced increase in the expression of BDNF and NKCC1/KCC2 ratio and the reduction in KCC2 expression in these brain regions. In addition, ANA12 (0.25 or 0.50 mg/kg) reduced the LPS-induced cognitive deficit and depressive-like behaviors measured by a reduced spontaneous alternation in the Y-maze and increased immobility duration in TST and FST. Coadministration of PNU120596 (1 mg/kg) and ANA12 (0.25 mg/kg) prevented the LPS-induced cognitive deficit and depressive-like behaviors. Overall, PNU120596 prevented the LPS-induced depressive-like behavior by likely decreasing neuronal excitability via targeting microglial α7 nAChR in the hippocampus and prefrontal cortex.

Mice Lacking TAAR1 Show No Early Behavioral Response to Acute Restraint Stress

The role of the TAAR1 receptor, one of the trace amine-associated receptors (TAARs) family, in the formation of the behavioral component of the stress response was studied. The behavior of female TAAR1 knockout mice and wild-type (WT) mice was investigated in tests of elevated plus maze and elevated zero maze (EPM and EZM) and forced swimming test (FST) under normal conditions and after uncontrolled restraint stress exposure for 30 min. In the EPM test, the initial level of locomotor and exploratory activity, as well as the anxiety, was identical in both groups of mice. In the EZM test, the initial indicators of anxiety in female TAAR1 KO mice compared to female WT mice were higher, and locomotor activity was lower. When testing mice in the EZM 30 minutes after the end of stress exposure, it was found that the anxiety in female WT mice sharply increased, and the indicators of locomotor activity and exploratory behavior significantly decreased. The behavioral indicators in the EZM test in TAAR1 KO mice before and after stress were identical. A pronounced behavioral component of the stress response was observed in both TAAR1 KO and WT mice during testing in EPM. There were no significant differences between TAAR1 KO and WT mice during testing in EPM four hours after stress exposure. In the FST test the latency to the first immobility was initially longer in TAAR1 KO mice compared to the WT mice, but 24 h after the stress this indicator has significantly decreased. As a result, TAAR1 KO and WT mice no longer differed in all behavioral indicators in the FST. Three weeks after acute restraint stress, both TAAR1 KO and WT groups showed a significant increase in immobility duration and a decrease in latency to the first immobility, however no difference between the both groups of animals were found. Thereby, we found the complete absence of behavioral change immediately after stressor exposure in TAAR1 KO compared to the WT mice.

CRISPR/Cas9 based gene editing of Frizzled class receptor 6 (FZD6) reveals its role in depressive symptoms through disrupting Wnt/β-catenin signaling pathway

IntroductionAs one of the common psychiatric diseases, depression poses serious threats to human health. Although many genes have been nominated for depression, few of them were investigated in details at the molecular level. ObjectivesTo demonstrate Frizzled class receptor 6 (FZD6) functions in depression through disrupting Wnt/β-catenin signal pathway. MethodsThe FZD6 edited cell line and mouse model were generated by using CRISPR/Cas9 technique. The expression of key genes and proteins in Wnt/β-catenin pathway was determined by qRT-PCR and Western blotting, respectively. Animal behavioral tests, including open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), tail suspension test (TST), and sucrose preference test (SPT), were employed to determine anxiety- and depressive-like behaviors. Immunofluorescent staining was used to assess cell proliferation in the hippocampus of mouse brain. ResultsAmong patients with depression, FZD6, one of the receptors of Wnt ligand, was significantly decreased. In CRISPR/Cas9-based FZD6 knockdown cells, we showed that FZD6 plays a significant role in regulating expression of genes involved in Wnt/β-catenin pathway. Subsequently behavioral studies on Fzd6 knockdown mice (with a 5-nucleotide deletion; Fzd6-Δ5) revealed significant changes in depressive symptoms, including increased immobility duration in FST, less preference of sucrose in SPT, reduction of distance traveled in OFT, and decreased time spent in open arms in EPM. Immunofluorescent staining showed decreased cell proliferation in the hippocampus of Fzd6-Δ5 mice with reduced number of Ki67+ and PCNA+ cells.Moreover, decreased Gsk3β mRNA expression, phosphorylated GSK3β, and cytoplasmic β-catenin in the hippocampus of Fzd6-Δ5 mice provided further evidence supporting the role of Fzd6 in depression. ConclusionTogether, above findings proved the significant role of FZD6 in depression through its effect on hippocampal cell proliferation and its ability to regulate canonical Wnt/β-catenin pathway.

Effects of Empagliflozin on a Model of Chronic Depression and Brain Toll-Like Receptors Gene Expression in Male Rats

Background: Empagliflozin is an antidiabetic medication having anti-inflammatory and antioxidant properties. Objectives: To develop a chronic unpredictable stress (CUS) model in male rats, evaluate empagliflozin’s antidepressant effects, and describe the link between stress, an antioxidant enzyme, and Toll-like receptor (TLR)-4 gene expression in male rats. Materials and Methods: In this experiment, 50 rats were divided into five groups: G1–G5. The forced swimming test (FST) was used to examine the antidepressant effects of fluoxetine and empagliflozin, and real-time polymerase chain reaction was used to measure TLR-4 gene expression. FST was performed on each rat on days 0, 10, and 25. CUS was performed on each rat for 24 days. Results: By the end of day 10, all animals subjected to the CUS program had a substantial (P < 0.05) increase in immobility duration compared with day 0. The immobility duration in the CUS group was statistically significantly greater than the baseline. Stressed rats demonstrated a statistically significant reduction in immobility duration compared with CUS group G2. In comparison to the CUS group, fluoxetine significantly reduced immobility duration (P < 0.05). In terms of gene expression, the mean of fold changes in TLR-4 mRNA level in group 2 was considerably greater than in group 1. When compared with group 2, the means of the fold changes in TLR-4 mRNA level were considerably lower in groups 3, 4, and 5. Conclusions: Empagliflozin has antidepressant-like effects and can counteract the impact of stress-induced TLR-4 overexpression in the hippocampus and elevate the activity of antioxidant enzymes in the brains of depressed rats.

Neuroprotective effect of hesperidin and its combination with coenzyme Q10 on an animal model of ketamine-induced psychosis: behavioral changes, mitochondrial dysfunctions, and oxidative stress

BackgroundPsychosis is a complex mental illness divided by positive symptoms, negative symptoms, and cognitive decline. Clinically available medicines are associated with some serious side effects which limit their use. Treatment with flavonoids has been associated with delayed onset and development, decreased risk, or increased improvement of various neuropsychiatric disorders including psychosis with negligible side effects. Therefore, the present study was aimed to investigate the protective effects of hesperidin (flavonoid) alone or its combination with coenzyme Q10 against ketamine-induced psychotic symptoms in mice.ResultsKetamine (50 mg/kg, i.p.) was given for 21 days to induce psychosis in Laca mice of either sex. Locomotor activity and stereotypic behaviors, immobility duration (forced swim test), and increased transfer latency (elevated plus maze) were performed to test the effect of hesperidin (50 mg/kg, 100 mg/kg, 200 mg/kg, p.o.) and coenzyme Q10 (20 mg/kg, 40 mg/kg, p.o.) and combination of hesperidin + coenzyme Q10 followed by biochemical and mitochondrial complexes assays. For 21 days, ketamine (50 mg/kg, i.p.) administration significantly produced increased locomotor activity and stereotypic behaviors (positive symptoms), increased immobility duration (negative symptoms) and cognitive deficits (increases transfer latency) weakens oxidative defense and mitochondrial function. Further, 21 days’ administration of hesperidin and coenzyme Q10 significantly reversed the ketamine-induced psychotic behavioral changes and biochemical alterations and mitochondrial dysfunction in the discrete areas (prefrontal cortex and hippocampus) of mice brains. The potential effect of these drugs was comparable to olanzapine treatment. Moreover, the combination of hesperidin with coenzyme Q10 and or a combination of hesperidin + coenzyme Q10 + olanzapine treatment did not produce a significant effect compared to their per se effect in ketamine-treated animals.ConclusionsThe study revealed that hesperidin alone or in combination with coenzyme Q10 could reduce psychotic symptoms and improve mitochondrial functions and antioxidant systems in mice, suggesting neuroprotective effects against psychosis.

Behavioral Effects of Buspirone in Juvenile Zebrafish of Two Different Genetic Backgrounds.

Anxiety continues to represent a major unmet medical need. Despite the availability of numerous anxiolytic drugs, a large proportion of patients do not respond well to current pharmacotherapy, or their response diminishes with chronic drug application. To discover novel compounds and to investigate the mode of action of anxiolytic drugs, animal models have been proposed. The zebrafish is a novel animal model in this research. It is particularly appropriate, as it has evolutionarily conserved features, and drug administration can be employed in a non-invasive manner by immersing the fish into the drug solution. The first step in the analysis of anxiolytic drugs with zebrafish is to test reference compounds. Here, we investigate the effects of buspirone hydrochloride, an anxiolytic drug often employed in the human clinic. We utilize two genetically distinct populations of zebrafish, ABSK, derived from the quasi-inbred AB strain, and WT, a genetically heterogeneous wild-type population. We placed juvenile (10–13-day, post-fertilization, old) zebrafish singly in petri dishes containing one of four buspirone concentrations (0 mg/L control, 5 mg/L, 20 mg/L or 80 mg/L) for 1 h, with each fish receiving a single exposure to one concentration, a between subject experimental design. Subsequently, we recorded the behavior of the zebrafish for 30 min using video-tracking. Buspirone decreased distance moved, number of immobility episodes and thigmotaxis, and it increased immobility duration and turn angle in a quasi-linear dose dependent but genotype independent manner. Although it is unclear whether these changes represent anxiolysis in zebrafish, the results demonstrate that behavioral analysis of juvenile zebrafish may be a sensitive and simple way to quantify the effects of human anxiolytic drugs.

Antidepressant activity of ciprofloxacin and levofloxacin by using tail suspension test in Swiss albino mice on chronic administration

Introduction: Depression is evidenced by decreased mood and reduced activity that can affect person's thoughts, behavior, feelings, and also sense of well-being in the society. Use of long term antidepressant agent pose a significant adverse effect to vital organs hence safer drugs with antidepressant property is the need of the hour. Objectives: To evaluate antidepressant activity of Ciprofloxacin and Levofloxacin by using Tail suspension test in Swiss albino mice on chronic administration. Materials and Methods: Animals (Swiss albino mice) weighing in between the range of 25 to 30gms were selected for the study and administered the drugs, viz Control-1% Gum acacia, 10ml/kg, Standard- Imipramine, 10mg/kg, and compared with Ciprofloxacin (25 & 50mg/kg) and Levofloxacin (25 & 50mg/kg). All the drugs orally were administered once a day for 9 days and on 10th day, screened for antidepressant activity by suspending it from a rod 50cm above the ground and its mobility and immobility time was recorded over a six minutes’ observation by discarding initial two minutes’ observation to avoid bias. Statistics: Increases in the mobility time and decrease in immobility was considered as statistically significant result based on ANOVA (post hoc Dunnet’s test) statistical test with a significance probability of p value Results: Ciprofloxacin at 25mg/kg & 50 mg/kg has shown significant antidepressant activity with increase in duration of immobility with 64.00 ± 2.83 & 50.50 ± 1.50 sec with a p value of Conclusion: In our study, we identified the potent and efficacious antidepressant activity of an antimicrobial drug viz Ciprofloxacin and Levofloxacin as antidepressant drug. Keywords: Antidepressant, Ciprofloxacin, Levofloxacin, Tail suspension test.

Screening of Anxiolytic and Antidepressant of Methanolic Leaves Extract of Syzygium Cumini in Mice

Background: Anxiety and depression are very common in clinical practice and reduce the overall quality of life. In recent years, various researchers have focused on natural products which are derived from medicinal plants. Studies suggested that diet rich in flavonoids, vitamins and antioxidants are the important components in reduction of anxiety and depression.
 Objective: Hence current investigation was aimed to assess the anxiolytic and antidepressant effects of Syzygium cumini in mice at 125, 250 and 500 mg/kg.
 Methods: These effects were mainly evaluated twice at 8th and 15th days by elevated plus maze, open field test, forced swimming test and tail suspension test.
 Results and Conclusion: In open field test S. cumini showed escalation rearing in numbers and its duration which indicates improved exploratory behavior and locomotor activity of the animals. In EPM, there was increase in entries numbers and time spent in open arm. Decrease in immobility duration observed at low dose while high dose increased immobility duration in FST. Hence outcomes of current study indicate that S. cumini have anxiolytic and anti-depressant effect.

Administration of ethanolic extract of Erythrophleum ivorense (A Chev.) stem bark to male Wistar rats alters brain areas involved in motor coordination, behavior, and memory

Ethnopharmacological relevanceErythrophleum ivorense (A Chev.) is a common plant in the tropics. Its use as ordeal poison in folklore medicine is controversial. The incoordination and behavioral changes following consumption are often associated with guilt. This study is aimed at dispelling or upholding this belief by investigating the actions of E. ivorense on the brain and behavior using rat model. Materials and methodsSixty male Wistar rats were equally divided into five groups; control group received distilled water, test groups were administered 10, 20, 30 and 40 mg/kg ethanolic extract of E. ivorense in a daily oral dose for 28 days. Cognition (Morris water maze) depression (forced swim test), motor function (hanging wire and inverted wire mesh grid grip tests) and exploratory assessments were done. Brains were stained with H&E, Cresyl violet and immunohistochemistry was done using GFAP, anticalbindin-D28k, Iba-1 and MBP antibodies. ResultsAt all doses, E. ivorense significantly (P ≤ 0.05) increased escape latency in the Morris water maze compared to control. Forced swim test showed a dose-related increase in duration of immobility, significant reduction in hanging latency in hanging wire and wire mesh grid grip test was also observed. Depletion of Purkinje cells of the cerebellum and hippocampal neurons was observed with H&E and cresyl violet. Immuno-staining revealed astrocytic activation in the cerebellum, loss of dendritic spines, cortical microglial activation and demyelination in the cerebellum and dentate gyrus of the hippocampus. ConclusionThe ethanolic extract of E. ivorense stem bark caused a dose-dependent deficit in learning, memory and motor coordination with evidences of depression in rats. It is concluded that the plant is neurotoxic and induce several neurobehavioral changes.

The Antidepressant Effect of Chlorella vulgaris on Female Wistar Rats (Rattus norvegicus Berkenhout, 1769) with Chronic Unpredictable Mild Stress Treatment

Depression is a disabling mental disorder, predicted to become the world's number 2 disability by 2020 by the World Health Organization (WHO, 2018). Chronic stress is one of the triggers for depression, causing an imbalance in brain chemicals and antioxidants levels. Although antidepressant is a common treatment, discomforting side effects has compromised its efficacy, prompting the search for alternative medicines. Chlorella vulgaris is a microalgae famous for its excellent protein and antioxidant content. In this study, C. vulgaris (360 mg/kg p.o.) potency of antidepressant in chronic unpredictable mild stress (CUMS) model of depression in female rats was evaluated compared to amitriptyline (2,25 mg/kg p.o.) for 14 days. Two types of C. vulgaris namely cultivation sourced and commercially-sold, were used. Sucrose preference test, forced swim test (FST) and open field test (OFT) were used as depression-like behaviour test to validate C. vulgaris effect. Adrenal glands were observed to further understand its effect on the stress organ. The CUMS method produced rats with depressive-like behaviour evidently by reduced body weight, sucrose preference, exploring behaviour in OFT, and increased immobility duration in FST. Furthermore, an increase in adrenal weight, fasciculata zone, and reticularis zone was observed. Both C. vulgaris significantly (p<0,05) reversed depressive-like behaviour in rats subjected to CUMS, but not the size of adrenal glands. This finding indicated both types of C. vulgaris has the potential to be an alternative antidepressant but because of the short duration of treatment, it’s speculated that C. vulgaris may not have exhibited enough difference structurally yet.

Study on antidepressant activity of chiisanoside in mice

The antidepressant-like effect of chiisanoside from the leaves of Acanthopanax sessiliflorus was evaluated by using mice models of depression, forced swim test (FST) and tail suspension test (TST). The results showed that treatment with chiisanoside at dose of 5.0 mg/kg significantly decreased immobility time in the FST and TST. Pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist) and N-methyl-D-aspartic acid (NMDA, an agonist at the glutamate site) effectively reversed the antidepressant-like effect of chiisanoside (5.0 mg/kg). Moreover, chiisanoside treatment did not change the locomotor activity. And chiisanoside (5.0 mg/kg) also effectively increased the dopamine (DA) and γ-aminobutyric acid (GABA) levels in mice brains exposed to the FST and TST in the co-treatment groups. Then we designed lipopolysaccharide (LPS)-induced antidepressant behavioral experiment, the results showed that LPS significantly increased immobility duration in the TST and FST. Chiisanoside administration could effectively reduce serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels; at the same time, the changes of related indexes of oxidative stress are improved, such as superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, chiisanoside effectively down-regulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and nuclear factor-κB (NF-κB) in hippocampal. In conclusion, chiisanoside displayed significant antidepressant-like effect, which was probably related to the DAergic, GABAergic and glutamatergic systems. And the mechanism of anti-depressant effect of chiisanoside might be via the alterations of animal behaviors, hippocampus inflammation, oxidative stress and neurotrophy, which might be attributed by the BDNF/TrkB/NF-κB pathway.

Antidepressant and anxiolytic effects of Garcinia indica fruit rind via monoaminergic pathway

Depression and anxiety are the most crippling neuropsychiatric disorders of this modern era. These mostly occur as anxiety followed by depression or in mixed state. Therefore, there is an urgent need of a safe and effective treatment, which proves its worth in this ailment. What else than a conventional food would be a better choice for a convenient therapy. Therefore, Garcinia indica, commonly known as Kokam, fruit rind has been used in the present study to investigate its antidepressant and anti-anxiety potential using forced swim test, tail suspension test, and reserpine-induced hypothermia; and elevated plus maze, hole-board test, and light dark model, respectively. Garcinia indica fruit rind given to mice with food for consecutive 14 days at 0.5, 1, and 2% w/w significantly (p < 0.05) reduced despair behavior in forced swim test, immobility duration in tail suspension test, and also switched the hypothermia (reserpine induced) to normal temperature significantly (p < 0.05). Garcinia indica significantly (p < 0.05) raised the time elapsed and count of entries in open arms of elevated plus maze, enhanced incidence of head dipping in holes of hole board along with duration of expending time in lit compartment of light dark model, exhibiting its anti-anxiety effect. Garcinia indica significantly reduced monoamine oxidase and malondialdehyde levels providing support to neuroprotective potential of fruit rind. The mechanistic study showed the participation of G. indica at α1-adrenoceptor and D2-dopamine receptor, by attenuating prazosin and sulpiride-induced increase in immobility duration. Garcinia indica fruit rind showed a significant antidepressant and anxiolytic effect while no effect on locomotor activity, i.e., no psycho-stimulation.

Paeonol attenuates lipopolysaccharide-induced depressive-like behavior in mice

The present study was designed to detect the anti-depressant effects of paeonol and the possible mechanisms in the lipopolysaccharide-induced depressive-like behavior. Open-field test(OFT), tail suspension test(TST) and forced swimming test(FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in mice hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that LPS significantly decreased the levels of 5-HT and NE in the hippocampus. LPS also reduced open-field activity, as well as increased immobility duration in FST and TST. Paeonol administration could effectively reverse the alterations in the concentrations of 5-HT, NE and reduce the IL-6 and TNF-α levels. Moreover, paeonol effectively downregulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and Nuclear factor-κB (NF-κB) in hippocampal. In conclusion, paeonol administration exhibited significant antidepressant-like effects in mice with LPS-induced depression.

Pro- and Anticonvulsant Effects of the Ant Dinoponera quadriceps (Kempf) Venom in Mice.

Epilepsy affects at least 50 million people worldwide, and the available treatment is associated with various side effects. Approximately 20-30% of the patients develop seizures that persist despite careful monitored treatment with antiepileptic drugs. Thus, there is a clear need for the development of new antiepileptic drugs, and the venoms can be an excellent source of probes. In this context, while there are studies on venoms from snakes, scorpions, and spiders, little is known regarding venom from ants. The aim of this study was to investigate the potential pro- and anticonvulsant effects of the venom from the ant Dinoponera quadriceps (Kempf) in Swiss mice. After the injection of the crude venom (DqTx-5, 50, and 500mg/mL) in the lateral ventricle of mice, we observed a reduction of exploration and grooming behaviors, as well as an increase in immobility duration. In addition, the crude venom induced procursive behavior and tonic-clonic seizures at the highest concentration. Conversely, the preadministration of the denatured venom (AbDq) at the concentration of 2mg/mL protected the animals against tonic-clonic seizures (66.7%) and death (100%) induced by administration of bicuculline. Taken together, the findings demonstrate that D. quadriceps venom might be potential source of new pro- and anticonvulsants molecules.

Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood

Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is used in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased anxiety-like behavior in adulthood.

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression.

To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression. 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments. The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group. 6z is a novel 5-HT3 receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.

Repeated forced swim stress has additive effects in anxiety behavior and in cathecolamine levels of adult rats exposed to deltamethrin

Deltamethrin (DTM) is a type II pyrethroid insecticide that elicits autonomic and neuroendocrine responses that indicate high levels of stress, presumably caused by the neurotoxic effect of the insecticide. This study investigated the effect of DTM exposure (10mg/kg, p.o.) and an additional stress induced in the forced swim test (FST) in behavioral tasks related to anxiety, serum corticosterone levels, and striatal neurotransmitter levels. Open field behavior and social interaction were evaluated after DTM administration (10mgkg−1, p.o). DTM per se reduced rearing frequency in the open field, but no alterations in locomotion frequency or immobility duration were detected. Stress increased immobility duration compared with non-stressed animals. DTM reduced social interaction and increased corticosterone levels, and these effects were enhanced in stressed animals. Mainly stress affected dopaminergic and serotoninergic activity. In anxiety behavior and in both neurotransmitters and metabolites levels it was observed an additive effect of stress in DTM treated rat data. These results indicate that DTM enhanced the anxiogenic responses and stress had an additive effect over the DTM stress. The neurochemical data did not indicate an interaction between stress and DTM exposure. The present results may be important for implementing pyrethroid insecticide safety standards.

Antidepressant-like effect of essential oil of Perilla frutescens in a chronic, unpredictable, mild stress-induced depression model mice

Perilla frutescens (Perilla leaf), a garnishing vegetable in East Asian countries, as well as a plant-based medicine, has been used for centuries to treat various conditions, including depression. Several studies have demonstrated that the essential oil of P. frutescens (EOPF) attenuated the depressive-like behavior in mice. The present study was designed to test the anti-depressant effects of EOPF and the possible mechanisms in an chronic, unpredictable, mild stress (CUMS)-induced mouse model. With the exposure to stressor once daily for five consecutive weeks, EOPF (3, 6, and 9 mg·kg−1) and a positive control drug fluoxetine (20 mg·kg−1) were administered through gastric intubation to mice once daily for three consecutive weeks from the 3rd week. Open-field test, sucrose consumption test, tail suspension test (TST), and forced swimming test (FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in mouse hippocampus were determined by HPLC–ECD. Serum interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). The results showed that CUMS significantly decreased the levels of 5-HT and 5-HIAA in the hippocampus, with an increase in plasma IL-6, IL-1β, and TNF-α levels. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. EOPF administration could effectively reverse the alterations in the concentrations of 5-HT and 5-HIAA; reduce the IL-6, IL-1β, and TNF-α levels. Moreover, EOPF could effectively reverse alterations in immobility duration, sucrose consumption, and open-field activity. However, the effect was not dose-dependent. In conclusion, EOPF administration exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of EOPF might be related to the relation between alteration of serotonergic responses and anti-inflammatory effects.

Anti-depressant effect of hesperidin in diabetic rats.

This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.