Sucrose Preference Research Articles

PERK inhibitor (ISRIB) improves depression-like behavior by inhibitions of HPA-axis over-activation in mice exposed to chronic restraint stress

Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the treatment of depression. Although previous study showed the role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation related depression, its involvement in the neuropathology of chronic stress induced depression is still unknown. We tried to explore whether block the PERK pathway would alleviate the animals’ depression-like behavior induced by chronic restraint stress (CRS) and investigate the underlying mechanism. The CRS-exposed mice exhibited depression-like behavior, including anhedonia in the sucrose preference test (SPT), and increased immobility time in tail suspension test (TST) and forced swim test (FST). ISRIB administration for 2 weeks significantly improved the depression-like behavior in male mice exposed to CRS, which was manifested by markedly increasing the sucrose preference and reducing the immobility time in the FST and TST. However, we observed that exposure to the same dose of ISRIB in CRS female mice only showed improved anhedonia-like deficits,leaving unaltered improvement in the FST and TST. Mechanically, we found that ISRIB reversed the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, indicating decreased levels of serum corticosterone, reduced hippocampal glucocorticoidreceptor (GR) expression and expression of FosB in hypothalamic paraventricularnucleus (PVN), which was accompanied by preserved hippocampal neurogenesis. The present findings further expand the potential role of ER stress in depression and provide important details for a therapeutic path forward for PERK inhibitors in mood disorders.

Effects of chronic intermittent cold stress on anxiety-depression-like behaviors in adolescent rats

Stress, which triggers numerous physiological and behavioral responses in the organism, is a significant risk factor that contributes to the development of psychiatric disorders such as depression and anxiety. This study aimed to investigate the inflammation, oxidative stress status, anxiety, and depression-like behaviors of adolescent rodents exposed to chronic intermittent cold stress. Adolescent male rats were subjected to a modified chronic intermittent cold stress model (21 days, 1 hour/day, 4 °C). Depression-like behaviors were evaluated using the sucrose preference and forced swimming tests, while anxiety-like behaviors were assessed using the open field, elevated plus maze, and light-dark box tests. We measured levels of cortisol, tumor necrosis factor-α, interleukin-1β, brain-derived natriuretic factor, reactive oxygen species, malondialdehyde, total oxidants and antioxidants, and other chemicals in the prefrontal cortex, thalamus, striatum, and hippocampus brain regions of rats using ELISA and colorimetric methods. Data were analyzed using Student’s t-test and Pearson correlation analysis. After the cold stress treatment, both anxiety and depression-like behaviors increased remarkably in the subjects. Our study revealed significant changes in various brain regions among the stress-exposed subjects. Cold stress resulted in decreased BDNF levels in the prefrontal cortex and striatum (p < 0.05), increased cortisol levels in the prefrontal cortex (p < 0.05), increased IL-1β levels in the hippocampus and thalamus (p < 0.05), increased protein carbonyl levels in the striatum (p < 0.05), and decreased TAS in the prefrontal cortex and thalamus (p < 0.05). Adolescent rats exposed to cold exhibit both anxiety- and depression-like behaviors. This study observed an increase in inflammation in various brain regions, yet the responses to stress varied. Our findings suggest that adolescence is a period of heightened sensitivity to stress, which can lead to dramatic consequences.

Antidepressant-like effects of Cimicifuga dahurica (Turcz.) Maxim. via modulation of monoamine regulatory pathways

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways.

Ketamine as a treatment of stress-induced maternal depression in mice: effects on offspring behaviour

Maternal depression during pregnancy adversely affects offspring neurodevelopment and behaviour. Typical antide-pressants like selective serotonin reuptake inhibitors have limitations due to risks of crossing the placenta. Ketamine has emerged as a promising alternative treatment. This research examined ketamine's effects on offspring of mater¬nally stressed mice. Dams were divided into control, maternal adversity, fluoxetine, and ketamine groups. Open field, sucrose preference, elevated plus maze, and forced swim tests assessed offspring anxiety, anhedonia, and despair. Maternal adversity increased anxiety-like behaviours and ketamine or fluoxetine reversed some effects. However, fluoxetine more effectively mitigated despair in forced swim tests. Ketamine moderately alleviated anhedonia versus controls. Further research on dose-response and timing is needed to optimize ketamine treatment. Mitigating maternal depression is crucial for preventing maladaptive offspring neurobehavioral trajectories.

KeYu ShuShen Granule alleviates symptoms of depression by targeting the mTOR pathway in a rat model of depression induced by chronic unpredictable mild stress

BackgroundKeYu ShuoShen Granules (KSG) is a traditional Chinese medicine formula with radix bupleuri as the kingpin, which is widely used in the treatment of depression, but its exact mechanism of action is not yet fully understood. The aim of this study is to investigate the therapeutic mechanisms of KSG in a model of depression in rats. MethodsRats were equally divided into 5 groups including control, model, fluoxetine, KSG at high and low doses, chronic unpredictable mild stress combined with solitary rearing for 28 days was used to prepare a rat model of depression followed by 14 days of continuous gavage and modelling, and the antidepressant effects of KSG were analyzed using behavioral tests, proteomic techniques and pharmacological methods. ResultsAfter KGS treatment, the body weight, Sucrose Preference of the model rats increased significantly, and their motor and learning memory abilities were significantly improved in the open field test and Morris water maze (P<0.01 or P<0.05); At the same time, proteomics revealed a total of 7 differential proteins, 3 differential pathways, including Agps, Eif4e2, Pter, Sys1, Rgcc, Polr1d and Npy1r, mTOR signalling pathway, insulin signalling pathway, and human papillomavirus infection; the expression of p-mTOR, mTOR, and Eif4e2 was significantly up-regulated after drug administration (P<0.01 or P<0.05), and neuronal damage in the cerebral cortex was significantly restored. ConclusionKSG improved depression symptoms in model rats by modulating protein synthesis processes involved in the mTOR pathway and Eif4e2, producing a combined effect on the nervous system. This finding provides new theoretical support and a mechanistic explanation for the use of KSG in the treatment of depression.

The antipsychotic potential of Salix Mucronata on ketamine-induced rats

Salix mucronata is one of the herbal plants offered by the traditional health practitioners in KwaZulu-Natal, South Africa for the treatment of schizophrenia. This study aimed to investigate the effects of repeated administration of ketamine on social interaction, novelty and motivation in adult, male Sprague Dawley rats. It also aimed to investigate the potential of risperidone and the herbal extract of S. mucronata to reverse impairments that are induced by ketamine. Experimental rats (n=45) received a dose of ketamine at 30 mg/kg via intraperitoneal injection for 5 consecutive days. They were then allocated into their respective treatment groups and given risperidone (APD) and the herbal extract of S. mucronata (TM) at doses of 6 mg/kg and 5 mg/kg, respectively, for 7 consecutive days. Social behaviour was tested using the 3-chambered sociability test, and anhedonia was tested using the sucrose preference test. Ketamine induction elicited social withdrawal and reduced social novelty which were later successfully reversed by risperidone and S. mucronata. The rats showed reduced preference to sucrose post-induction and post-treatment. Ketamine and mild stress caused by scruff restraint elicited reduced weight gain for the animals. No differences were noted on brain mass between controls and experimental groups and also between risperidone and S. mucronata groups. However, reduced brain volume was noted in experimental groups. Dopamine and acetylcholine concentration levels were high in groups which received risperidone and S. mucronata. These findings highlight that the antipsychotic potential of S. mucronata is similar to risperidone.

L-type calcium channel regulation of depression, anxiety and anhedonia-related behavioral phenotypes following chronic stress exposure

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure.

In Vitro and In Vivo Anti-Inflammatory and Antidepressant-like Effects of Cannabis sativa L. Extracts.

Cannabis sativa L. has been widely used by humans for centuries for various purposes, such as industrial, ceremonial, medicinal, and food. The bioactive components of Cannabis sativa L. can be classified into two main groups: cannabinoids and terpenes. These bioactive components of Cannabis sativa L. leaf and inflorescence extracts were analyzed. Mice were systemically administered 30 mg/kg of Cannabis sativa L. leaf extract 1 h before lipopolysaccharide (LPS) administration, and behavioral tests were performed. We conducted an investigation into the oxygen saturation, oxygen tension, and degranulation of mast cells (MCs) in the deep cervical lymph nodes (DCLNs). To evaluate the anti-inflammatory effect of Cannabis sativa L. extracts in BV2 microglial cells, we assessed nitrite production and the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The main bioactive components of the Cannabis sativa L. extracts were THCA (a cannabinoid) and β-caryophyllene (a terpene). Cannabis sativa L. leaf extract reduced the immobility time in the forced swimming test and increased sucrose preference in the LPS model, without affecting the total distance and time in the center in the open field test. Additionally, Cannabis sativa L. leaf extract improved oxygen levels and inhibited the degranulation of MCs in DCLNs. The Cannabis sativa L. extracts inhibited IL-1β, IL-6, TNF-α, nitrite, iNOS, and COX-2 expression in BV2 microglia cells. The efficacy of Cannabis sativa L. extracts was suggested to be due to the entourage effect of various bioactive phytochemicals. Our findings indicate that these extracts have the potential to be used as effective treatments for a variety of diseases associated with acute inflammatory responses.

FMOD Alleviates Depression-Like Behaviors by Targeting the PI3K/AKT/mTOR Signaling After Traumatic Brain Injury

Depression frequently occurs following traumatic brain injury (TBI). However, the role of Fibromodulin (FMOD) in TBI-related depression is not yet clear. Previous studies have suggested FMOD as a potential key factor in TBI, yet its association with depression post-TBI and underlying mechanisms are not well understood. Serum levels of FMOD were measured in patients with traumatic brain injury using qPCR. The severity of depression was assessed using the self-depression scale (SDS). Neurological function, depressive state, and cognitive function in mice were assessed using the modified Neurological Severity Score (mNSS), forced swimming test (FST), tail suspension test (TST), Sucrose Preference Test (SPT), and morris water maze (MWM). The morphological features of mouse hippocampal synapses and neuronal dendritic spines were revealed through immunofluorescence, transmission electron microscopy, and Golgi-Cox staining. The protein expression levels of FMOD, MAP2, SYP, and PSD95, as well as the phosphorylation levels of the PI3K/AKT/mTOR signaling pathway, were detected through Western blotting. FMOD levels were decreased in TBI patients’ serum. Overexpression of FMOD preserved neuronal function and alleviated depression-like behaviour, increased synaptic protein expression, and induced ultrastructural changes in hippocampal neurons. The increased phosphorylation of PI3K, AKT, and mTOR suggested the involvement of the PI3K/AKT/mTOR signaling pathway in FMOD’s protective effects. FMOD exhibits potential as a therapeutic target for depression related to TBI, with its protective effects potentially mediated through the PI3K/AKT/mTOR signaling pathway.

Analysis of hippocampal synaptic function in a rodent model of early life stress.

Early life stress (ELS) is an important risk factor in the aetiology of depression. Developmental glucocorticoid exposure impacts multiple brain regions with the hippocampus being particularly vulnerable. Hippocampal mediated behaviours are dependent upon the ability of neurones to undergo long-term potentiation (LTP), an N-methyl-D-aspartate receptor (NMDAR) mediated process. In this study we investigated the effect of ELS upon hippocampal NMDAR function. Hooded Long-Evans rat pups (n=82) were either undisturbed or maternally separated for 180 minutes per day (MS180) between post-natal day (PND) 1 and PND14. Model validation consisted of sucrose preference (n=18) and novelty supressed feeding (NSFT, n=34) tests alongside assessment of corticosterone (CORT) and paraventricular nucleus (PVN) cFos reactivity to stress and hippocampal neurogenesis (all n=18). AMPA/NMDA ratios (n=19), miniEPSC currents (n=19) and LTP (n=15) were assessed in whole-cell patch clamp experiments in CA1 pyramidal neurones. MS180 animals showed increased feeding latency in the NSFT alongside increased overall CORT in the restraint stress experiment and increased PVN cFos expression in males but no changes in neurogenesis or sucrose preference. MS180 was associated with a lower AMPA/NMDA ratio with no change in miniEPSC amplitude or area. There was no difference in short- or long-term potentiation between MS180 and control animals nor were there any changes during the induction protocol. The MS180 model showed a behavioural phenotype consistent with previous work. MS180 animals showed increased NMDAR function with preliminary evidence suggesting that this was not concurrent with an increase in LTP.

Alteration of hyperpolarization-activated cation current-mediated metaplasticity contributes to electroconvulsive shock-induced learning and memory impairment in depressed rats.

Accompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported that metaplasticity is involved in this process. However, the mechanisms still remain unclear. This study investigated the role of I h current in the metaplastic changes and learning and memory impairment induced by ECS in depressive rats. Depressive rats received ECS after modelling using chronic unpredictable. ZD7288, a type of I h current inhibitor was used to verify the effect of I h current. The sucrose preference test and Morris water maze were used for behavior testing. Changes in metaplasticity was assessed with the LTD/LTP threshold by stimulation at different frequencies. Spontaneous and evoked action potentials (APs) were measured to confirm difference of neuronal excitability. Additionally, the amplitude of I h current was analyzed. ECS exerts antidepressant effect, but also induce spatial learning and memory dysfunction. ECS up-regulates the LTD/LTP threshold. In rats treated with ECS, the frequency of spontaneous and evoked APs is significantly reduced. In addition, ECS induces changes in the intrinsic properties of AP, including a decrease of AP-half width and peak amplitude, and an increase in AP time to peak and post-hyperpolarization potential amplitude. In particular, ECS increases both instantaneous and steady-state I h currents. However, Inhibition of I h current withZD7288 results in a relief of learning and memory impairment andadecreaseinthreshold, as well as a significant reversal of whole-cell electrophysiological changes. ECS-induced learning and memory impairment is caused by neuronal hypoexcitability mediated metaplasticity, and upregulation of LTD/LTP threshold by an increase in I h current.

NMT2 alleviates depression-like behavior in a rat model of chronic unpredictable stress: An integrated proteomic and phosphoproteomic analysis

Proteomics has been widely used to investigate multiple diseases. Combining the analyses of proteomics with phosphoproteomics can be used to further explain the pathological mechanisms of depression. In this study, depression-like behavior was induced in a rat model of chronic unpredictable mild stress (CUMS). We subsequently conducted the sucrose preference test, open field experiment, and forced swimming test to assess depressive-like behavior. Proteomic and phosphoproteomic sequencing of the hippocampal tissues from depressive-like behavior and normal rats were analyzed to identify differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs). Differentially expressed phosphorylated proteins (DEPPs) were obtained by intersecting the DEPs and DPPs, and functional enrichment analysis, as well as ingenuity pathway analysis (IPA), were subsequently performed. The study also investigated correlations among the DEPPs and used qRT-PCR to quantify the expression levels of key genes. Five DEPPs were identified, Gys1, Nmt2, Lrp1, Bin1, and Atp1a1, which were found to activate the synaptogenesis signaling pathway, induce mitochondrial dysfunction, and activate the phosphoinositide biosynthesis and degradation pathways. The qRT-PCR results confirmed the proteomic findings for Gys1, Nmt2, Lrp1, and Atp1a1. Importantly, inhibiting Nmt2 was found to alleviate depression-like behavior and alleviate neuronal apoptosis in the hippocampus of CUMS rats. In conclusion, we identified five DEPPs associated with the synaptogenesis signaling pathway, mitochondrial dysfunction, and phosphoinositide biosynthesis and degradation in depression. Furthermore, NMT2 may be a potential target for the treatment or diagnosis of depression. Our findings provide novel insights into the molecular mechanisms of depression.

DL-3-n-Butylphthalide Ameliorates Post-stroke Emotional Disorders by Suppressing Neuroinflammation and PANoptosis.

Post-stroke emotional disorders such as post-stroke anxiety and post-stroke depression are typical symptoms in patients with stroke. They are closely associated with poor prognosis and low quality of life. The State Food and Drug Administration of China has approved DL-3-n-butylphthalide (NBP) as a treatment for ischemic stroke (IS). Clinical research has shown that NBP alleviates anxiety and depressive symptoms in patients with IS. Therefore, this study explored the role and molecular mechanisms of NBP in cases of post-stroke emotional disorders using network pharmacology and experimental validation. The results showed that NBP treatment significantly increased the percentage of time spent in the center of the middle cerebral artery occlusion (MCAO) rats in the open field test and the percentage of sucrose consumption in the sucrose preference test. Network pharmacology results suggest that NBP may regulate neuroinflammation and cell death. Further experiments revealed that NBP inhibited the toll-like receptor 4/nuclear factor kappa B signaling pathway, decreased the level of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, and M1-type microglia markers (CD68, inducible nitric oxide synthase), and reduced the expression of PANoptosis-related molecules including caspase-1, caspase-3, caspase-8, gasdermin D, and mixed lineage kinase domain-like protein in the hippocampus of the MACO rats. These findings demonstrate that the mechanisms through which NBP ameliorates post-stroke emotional disorders in rats are associated with inhibiting neuroinflammation and PANoptosis, providing a new strategy and experimental basis for treating post-stroke emotional disorders.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype

The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity. Therefore, this study examined the effect of TCDD on depression-like behaviors. Female mice were fed standard chow or a high-fat diet (HFD) for 11 weeks, and their weight was recorded. Subsequently, they were tested for baseline sucrose preference and splash test grooming. Then, TCDD (0.1 µg/kg/day) or vehicle was administered orally for 28 days, and mice were examined for their sucrose preference and performances in the splash test, forced swim test (FST), and Morris water maze (MWM) task. TCDD significantly decreased sucrose preference, increased FST immobility time, and decreased groom time in chow-fed mice. HFD itself significantly reduced sucrose preference. However, TCDD significantly increased FST immobility time and decreased groom time in HFD-fed mice. A small decrease in bodyweight was observed only at the fourth week of daily TCDD administration in chow-fed mice, and no significant effects of TCDD on bodyweights were observed in HFD-fed mice. TCDD did not have a significant effect on spatial learning in the MWM. Thus, this study demonstrated that TCDD induces a depression-like state, and the effects were not due to gross lethal toxicity. This study further suggests that more studies should examine a possible role for AhR and AhR-active environmental pollutants in precipitating or worsening MDD.

The effects of venlafaxine on depressive-like behaviors and gut microbiome in cuprizone-treated mice.

Cuprizone (CPZ)-treated mice show significant demyelination, altered gut microbiome, and depressive-like behaviors. However, the effects of venlafaxine (Ven) on the gut microbiome and depressive-like behavior of CPZ-treated mice are largely unclear. Male C57BL/6J mice were fed a chow containing 0.2% cuprizone (w/w) for 5 weeks to induce a model of demyelination. Meanwhile, the gut microbiota and depressive-like behaviors were assessed after the mice were fed with Ven (20 mg/kg/day) or equal volumes of distilled water for 2 weeks by oral gavage from the third week onward during CPZ treatment. CPZ treatment decreased the sucrose preference rate in the sucrose preference test and increased the immobility time in the tail-suspension test, and it also induced an abnormality in β-diversity and changes in microbial composition. Ven alleviated the depressive-like behavior and regulated the composition of the gut microbiota, such as the increase of Lactobacillus and Bifidobacterium in CPZ-treated mice. The anti-depressant effects of Ven might be related to the regulation of gut microbiota in the CPZ-treated mice.

Stress enhances expression of calcium‐binding proteins and NMDAR subunit genes in the rat hippocampus

AbstractBackgroundsOxidative stress impairs the function of calcium‐binding proteins and deregulates calcium signaling in living organisms. We have previously explored the overexpression of calcium‐binding protein genes in a reactive oxygen and nitrogen species‐induced in vitro cell model of stress that leads to apoptosis. However, in in vivo models, low levels of stress leads to depressive‐like behavior. Here, we aimed to analyze gene expression of major calcium‐binding proteins (calcineurin, calmodulin, calsyntenin, synaptotagmin, and calreticulin) and N‐methyl‐d‐aspartic acid (NMDA) receptor subunits (glutamate receptor ionotropic [GluN] GluN1, GluN2A, and GluN2B) in the hippocampus of stress‐induced rats.MethodsSix‐week‐old male Wistar rats were assigned to two stress induction groups and a control group without stress (n = 6). Stress was induced by using H2O2 (3% in water) or by immobilization (using a sticky mat) over a period of 30 days. Expression of calcium‐binding protein genes in the hippocampus, antioxidant assays, structural alterations in hippocampal neurons, and depressive‐like behavior were determined.ResultsExpression of genes encoding calcium‐binding proteins calcineurin, calsyntenin, synaptotagmin and NMDA receptor subunit GluN1 was enhanced in both chemical and physical stress‐induced rats compared with control rats (4.25 ± 0.05 vs. 1.03 ± 0.02, p &lt; 0.05, 2.05 ± 0.08 vs. 1.03 ± 0.02, p &lt; 0.005; 2.2 ± 0.4 vs. 1.02 ± 0.03, p &lt; 0.05, 1.98 ± 0.07 vs. 1.02 ± 0.03, p &lt; 0.005; 1.4 ± 0.6 vs. 1.15 ± 0.09, p &lt; 0.05, 1.39 ± 0.05 vs. 1.15 ± 0.09, p &lt; 0.005), respectively. In stress‐induced rats, neurons in the CA2 region of the hippocampus were fewer and appeared disorganized compared with control rats. Furthermore, stress‐induced rats showed decreased mobility and lower sucrose preference in behavioral studies compared with control rats.ConclusionLower levels of reactive oxygen and nitrogen species (RONS) can also lead to stress in rats by affecting their calcium signaling, buffering capacity in the neurons leading to depressive symptoms.

Lycopene alleviates BCG-induced depressive phenotypes in mice by disrupting 5-HT3 receptor – IDO1 interplay in the brain

The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.

Effects of pre- versus post-conceptional iron and n-3 fatty acid supplementation of deficient rat dams on neurodevelopmental outcomes in the offspring

This abstract was awarded the Student Competition Prize.Periconception is the period spanning the weeks directly before and after conception and is a crucial window for optimising neurodevelopment in offspring(1-4). Iron and omega-3 fatty acids (n-3 FAs) are two vital nutrients for the development of the nervous system however, little research has been conducted into their importance during the periconceptional window(5-8). This study investigated whether supplementing iron and n-3 FA deficient (ID and n-3 FAD) rat dams before conception compared to after conception results in different neurodevelopmental outcomes in offspring. We hypothesised that initiating iron and n-3 FA supplementation in deficient dams after conception would not be as efficacious in preventing impaired offspring neurodevelopment induced by double- deficiency, compared to initiating supplementation before conception.Female rats consuming an ID and n-3 FAD diet were randomly allocated to receive iron and DHA/EPA supplementation either 10 days before (Pre-Fe+DHA/EPA) or 10 days after conception (Post-Fe+DHA/EPA). Dams and offspring (Pre-: n = 24; Post-: n = 26) were subsequently maintained on supplemented diets throughout the experiment. Between postnatal days 31–41, cognitive and behavioural tests were conducted on offspring. Offspring were euthanised between postnatal day 42–45 and n-3 FAs, iron and monoamine concentrations were measured in the hippocampus, striatum and frontal cortex. All outcomes were compared to offspring who were either iron and n-3 FA deficient (ID+n-3 FAD: n = 24) or sufficient (Control+Fe+DHA/EPA: n = 22). One-way ANCOVA, with sex as a covariate, was used to determine between-group differences and two-way ANOVA was used to explore diet-sex interactions.There were no differences in brain iron or n-3 FA levels between Pre- and Post-Fe+DHA/EPA offspring (P &gt; 0.05). Female Post-Fe+DHA/EPA offspring had greater norepinephrine concentrations in the frontal cortex (Pre-: 3.21 ± 0.57 ng/mg vs Post-: 2.50 ± 0.55 ng/mg; P = 0.014) and consumed less sucrose in the sucrose preference test (Pre-: 96.16 ± 1.73%; Post-: 90.15 ± 1.66%; P = 0.010) compared to Pre-Fe+DHA/EPA offspring. Female Post-Fe+DHA/EPA offspring also had significantly lower liver iron concentrations compared to female Pre-Fe+DHA/EPA offspring (Pre-: 537 ± 47.13 μg/L vs Post-: 310 ± 45.28 μg/L; P = 0.034). There were no other significant differences in monoamine concentrations or behavioural tests.Our results indicate that supplementing ID and n-3 FAD mothers both before and after conception is efficacious in preventing neurodevelopmental deficits associated with deficiency. However, ID and n-3 FAD during the periconceptional period may alter reward-based learning in female offspring(9-11). Additionally, optimising iron provision during periconception may have important implications for the prevention of postnatal ID-anaemia, particular during early infancy(12).

Chronic administration of caffeine, modafinil, AVL-3288 and CX516 induces time-dependent complex effects on cognition and mood in an animal model of sleep deprivation

ObjectiveCaffeine and modafinil are used to reverse effects of sleep deprivation. Nicotinic alpha-7 receptor and AMPA receptor positive allosteric modulators (PAM) are also potential substances in this context. Our objective is to evaluate the effects of caffeine, modafinil, AVL-3288 (nicotinic alpha-7 PAM) and CX516 (AMPA receptor PAM) on cognition and mood in a model of sleep deprivation. MethodModified multiple platform model is used to sleep-deprive mice for 24 days, for 8 h/day. Vehicle, Modafinil (40 mg/kg), Caffeine (5 mg/kg), CX516 (10 mg/kg), and AVL3288 (1 mg/kg) were administered intraperitoneally daily. A cognitive test battery was applied every six days for four times. The battery that included elevated plus maze, novel object recognition, and sucrose preference tests was administered on consecutive days. ResultsSleep deprivation decreased novel object recognition skill, but no significant difference was found in anxiety and depressive mood. Caffeine administration decreased anxiety-like behavior in short term, but this effect disappeared in chronic administration. Caffeine administration increased memory performance in chronic period. AVL group showed better memory performance in short term, but this effect disappeared in the rest of experiment. Although, in the modafinil group, no significant change in mood and memory was observed, anhedonia was observed in the chronic period in vehicle, caffeine and modafinil groups, but not in AVL-3288 and CX-516 groups. ConclusionCaffeine has anxiolytic effect in acute administration. The improvement of memory in chronic period may be associated with the neuroprotective effects of caffeine. AVL-3288 had a short-term positive effect on memory, but tolerance to these effects developed over time. Furthermore, no anhedonia was observed in AVL-3288 and CX516 groups in contrast to vehicle, caffeine and modafinil groups. This indicates that AVL-3288 and CX516 may show protective effect against depression.

Antidepressant Effect of Vincamine, Melatonin and their Combination in Experimental Rat Models of Depression

Background: Depression, a form of mood illness, is characterized by a lack of or diminished social life, melancholy, and symptoms linked to an uplifted or depressed mood. Vincamine and Melatonin combination may prove beneficial for treating depression because vincamine and melatonin have already been reported in the treatment of dementia. Dementia is a CNS disorder which is connected to the level of neurotransmitters at the synaptic cleft, which is similar to depression that is why it might be effective in the treatment of depression. Aim: The aim of this research is to conduct an experimental study on the antidepressant activity of Vincamine alone and along with Melatonin and comparison with standard antidepressant drugs. Method: In this study, all animals are trained for the experiment, and then animals are divided into groups according to the treatment protocol. Animals were placed for the rest for 1 week. Vincamine and melatonin were administered to the treated groups on days 8 and 21 for the behavioral analysis using different kinds of models like elevated plus maze, forced swim test, open field test and sucrose preference test. Animals were sacrificed at day 22 for the estimation of biochemical (SOD) and neurotransmitters (Serotonin, Norepinephrine and Dopamine). Results: After extensive investigation, it has been established that Vincamine, alone and in combination with Melatonin, is beneficial in treating depression. Positive results are obtained. The group treated with Vincamine taken per oral route ((10 mg/kg), Melatonin (10 mg/kg), Vincamine + Melatonin (10 mg/kg + 10 mg/kg) and std (10 mg/kg) treatment showed significant result which are followed as for all groups (a) p &lt; 0.0001 vs NC; (b) p &lt; 0.0001 vs disease control; (c) p &lt; 0.05 vs Std (10 mg/kg); (d) p &lt; 0.001V vs M (10 mg/kg); (e) p &lt; 0.0090 vs V+M (10 mg/kg+10 mg/kg). It was demonstrated by a number of behavioral (elevated plus maze, forced swim test, open field test, and sucrose preference test) and biochemical parameters (estimation of neurotransmitters such as serotonin, epinephrine, and dopamine). Vincamine alone and in combination with Melatonin demonstrated positive results (p &lt; 0.0001) in the evaluation of the SOD antioxidant defence system. Also, it significantly attenuated the alteration in locomotor activity, oxidative stress and neurotransmitters in rat brain. result: After extensive investigation, it has been established that Vincamine, alone and in combination with Melatonin, is beneficial in treating depression. Positive results are obtained. The group treated with Vincamine taken per oral route ((10mg/kg), Melatonin (10mg/kg), Vincamine + Melatonin (10mg/kg + 10mg/kg) and std (10mg/kg) treatment showed significant result which are followed as for all groups (a) p &amp;amp;lt; 0.0001 vs NC; (b) p &lt; 0.0001 vs disease control; (c) p &lt; 0.05 vs Std (10 mg/kg); (d) p &lt; 0.001V vs M (10 mg/kg); (e) p &lt; 0.0090 vs V+M (10mg/kg+10mg/kg). It was demonstrated by a number of behavioral (elevated plus maze, forced swim test, open field test, and sucrose preference test) and biochemical parameters (estimation of neurotransmitters such as serotonin, epinephrine, and dopamine). Vincamine alone and in combination with Melatonin demonstrated positive results (p&lt;0.0001) in the evaluation of the SOD antioxidant defence system. Also, significantly attenuated the alteration in locomotor activity, oxidative stress and neurotransmitters in rat brain. Conclusion: It has been concluded that vincamine alone and along with melatonin is effective for the treatment of depression on the basis of behavioural and biochemical parameters. That’s why it might be useful for the future prospect.