The antidepressant-like effects of an n-butanol fraction of Ocimum sanctum Linn. extract in unpredictable chronic mild stress-induced depression in mice

We previously reported that Ocimum sanctum Linn. (OS) ethanolic extract and its n-butanol fraction (OS-B) could improve depression-like behaviour in olfactory bulbectomized mice. The present study aims to clarify the antidepressant-like effects of OS-B and the possible mechanism of its action using mice subjected to unpredictable chronic mild stress (UCMS). UCMS mice were administered daily with OS-B (50 mg/kg, 100 mg/kg, p.o.) or imipramine (IMP, 8 mg/kg, i.p.), a reference drug. The UCMS-induced anhedonia in mice was analysed by the sucrose preference test, while behavioural despair was assessed using the tail suspension test (TST) and forced swimming test (FST). Locomotor activities and grooming behaviour of mice were elucidated using the open-field test (OFT). The UCMS procedure for 5 weeks induced anhedonia, and this symptom was significantly ameliorated by the administration of OS-B (100 mg/kg) as well as IMP during the UCMS period. Moreover, the OS-B and IMP treatment attenuated the UCMS-induced enhancement of behavioural despair in the TST and FST. In OFT, mice subjected to UCMS showed a decrease in grooming behaviour, and the effect of UCMS was reversed by OS-B and IMP administrations. No significant difference in locomotor activities between each animal group was observed. The amelioration effects of OS-B and IMP on UCMS-induced behavioural despair in the TST were abolished by administrating of ρ-chlorophenylalanine (PCPA, 80 mg/kg, i.p), a tryptophan hydroxylase inhibitor, and α-methyl-ρ-tyrosine (AMPT, 100 mg/kg), a tyrosine hydroxylase inhibitor. The present results suggest that OS-B attenuates UCMS-induced depression-like symptoms via monoaminergic systems including in the noradrenergic, dopaminergic, and serotonergic system

Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB816 in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling.

Behavior in mice subjected to a Token Slot-machine: effect of Unpredictable Chronic Mild Stress

Several studies have succeeded in teaching animals (primates, pigeons, rats, but not mice) the value of tokens by having them executing a task using a vending-machine apparatus, where in order to receive the primary reinforcement (food), the animals had to perform a specific action that allowed them to obtain the secondary reinforcement (tokens: metal balls). We tried to assess this kind of behavior in mice that had previously been trained to use some tokens, with the aim of rewarding them not with food, but with other tokens, as a result of a token economy task. We found that mice exhibit economic behavior. Further on, our research tried to investigate the effect of stress on their operant decision-making. Therefore, the mice were divided into two groups: a Control group (n=10) and a group subjected to an Unpredictable Chronic Mild Stress (UCMS) treatment (n=8). We found that chronic stress increases some aspects of sub-optimal economic activity.

Vitamin D3 administration prevents memory deficit and alteration of biochemical parameters induced by unpredictable chronic mild stress in rats

The present study aimed to investigate the effects of vitamin D3 (Vit D) administration on memory function, hippocampal level of amyloid-beta (Aβ), brain-derived neurotrophic factor (BDNF) and oxidative stress status in a rat model of unpredictable chronic mild stress (UCMS). Vit D was intraperitoneally administered at doses of 100, 1000, and 10,000 IU/kg. Animals were subjected to UCMS for a total period of 4 weeks. Memory function was assessed using morris water maze (MWM) and passive avoidance (PA) tests. Biochemical markers were measured to reveal the status of oxidative stress and antioxidant defense system. In addition, the levels of Aβ and BDNF were measured in hippocampal region. In the UCMS group, latency to find the platform was greater and the time spent in target quadrant (MWM test) as well as the latency to enter the dark compartment (PA test), were less than the vehicle group. Hippocampal malondialdehyde (MDA) and Aβ concentrations in the UCMS group were higher than the vehicle group. Hippocampal level of thiol and BDNF plus the activities of catalase and superoxide dismutase (SOD) were reduced in UCMS group compared to the control subjects (i.e. vehicle group). Interestingly, Vit D treatment supplementation reversed the mentioned effects of UCMS. Our findings indicated that Vit D administration improves UCMS-induced impairment of learning and memory through prevention of adverse effects on Aβ, BDNF and oxidative stress parameters.

Merging the Multi-Target Effects of Kleeb Bua Daeng, a Thai Traditional Herbal Formula in Unpredictable Chronic Mild Stress-Induced Depression

Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between genetics and environment involved. Kleeb Bua Daeng (KBD) is a Thai traditional herbal formula that has been used to promote brain health. It consists of a 1:1:1 ratio of the aerial part of Centella asiatica, Piper nigrum fruit, and the petals of Nelumbo nucifera. According to the pharmacological activities of the individual medicinal plants, KBD has good potential as a treatment for MDD. The present study investigated the antidepressant activity of KBD in an unpredictable chronic mild stress (UCMS) mouse model. Daily administration of KBD to UCMS mice ameliorated both anhedonia, by increasing 2% sucrose intake, and hopeless behavior, by reducing immobility times in the forced swimming test (FST) and tail suspension test (TST) without any effect on locomotor activity. The mechanism of KBD activity was multi-modal. KBD promoted neurogenesis by upregulation of brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding (CREB) mRNA expression in the frontal cortex and hippocampus. Daily treatment with KBD significantly reversed UCMS-induced HPA axis dysregulation by upregulating the glucocorticoid receptor (GR) while downregulating serum- and glucocorticoid-inducible kinase 1 (SGK1) and FK506 binding protein 5 (FKBP5) mRNA expression. KBD treatment also normalized proinflammatory cytokine expression including tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β and IL-6. KBD and its component extracts also exhibited an inhibitory effect in vitro on monoamine oxidase (MAO) A and B. The multiple antidepressant actions of KBD emphasize its potential as an effective, novel treatment for MDD.

The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

Rationale The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs. Objectives The antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT1A receptors and F13714, which targets 5-HT1A autoreceptors, were investigated in mice. Methods Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined. Results F15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4–16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels. Conclusions Our studies showed that 5-HT1A receptor biased agonists such as F13714 and especially F15599, due to its less pronounced side effects, might have potential as fast-acting antidepressants.

A Comparison of Isolation Stress and Unpredictable Chronic Mild Stress for the Establishment of Mouse Models of Depressive Disorder

This study aimed to help to understand the influence of stress on depression, which reflects the social environments of especially solitary life and the increasing prevalence of depressive disorders. To determine the distinguishable features of two-representative animal models of stress-induced depressive disorder, we compared isolation stress (IS) and unpredictable chronic mild stress (UCMS). After 4-week of stress, both models showed significant depressive- and anxiety-like behaviors in an open field test (OFT; p < 0.01 for IS, p < 0.01 for UCMS), forced swimming test (FST; p < 0.01 for IS, p < 0.01 for UCMS), and tail suspension test (TST; p < 0.01 for IS, p < 0.05 for UCMS) along with alterations in serum corticosterone levels, serotonin activity in the dorsal raphe nuclei (DRN) and microglial activity in the dentate gyrus of the hippocampus (p < 0.05 for both parameters). In a comparison of the two stress models, IS strongly induced depressive and anxiety features, as indicated by all parameters: behavior test scores (p < 0.05 for OFT, FST, and TST), serum corticosterone levels (p < 0.05), immunohistological alterations for serotonin activity (p < 0.05) and microglial activity (p = 0.072). Our results indicate the suitability of IS for the development of animal models of depressive disorders and may reveal the medical impact of social isolation environment in modern society.