The Forced Swim Test as a Model of Depressive-like Behavior

The goal of the present protocol is to describe the forced swim test (FST), which is one of the most commonly used assays for the study of depressive-like ...

The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice

Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by ...

Academic College of Tel Aviv-Yaffo

The Open University of Israel

Hadassah Academic College

The Academic College Tel-Aviv-Yaffo

Open University

Depression is a chronic, recurring and potentially life-threatening illness. Current treatments for depression are characterized by a low success rate and associated with a wide variety of side effects. The aim of the present study was to evaluate the behavioral and biological anti-depressant effects of a novel herbal treatment (NHT), as well as to assess its potential side effects, in comparison to treatment with the selective serotonin reuptake inhibitor escitalopram.

A novel herbal treatment reduces depressive-like behaviors and increases BDNF levels in the brain of stressed mice.

Traditional herbal medicine can offer efficacious and safe alternative pharmacotherapies for depression. The ability of an herbal medicine to produce neuroadaptive processes, that enhance neuroplasticity and cellular resilience in response to chronic stress, may point to its antidepressant potential. We suggest that among many investigated herbal medicines, those that can enhance neuroplasticity may have stronger therapeutic potential. The current article presents a summary of traditional herbal medicines, which are thought to exert antidepressant-like effects in chronic stress models via neuroplasticity enhancement. Brain-derived neurotrophic factor (BDNF) is a biomarker for neuroplasticity-related mechanisms compromised in depression and recovered by conventional antidepressants, including synaptic plasticity, cell survival, neurogenesis and spine formation. We therefore presumed that if an herbal medicine up-regulates BDNF in the hippocampus and/or prefrontal cortex (PFC), its antidepressant-like effect is mediated, at least partially, via neuroplasticity-related mechanisms. Literature search was performed using the general terms depression, stress, neuroplasticity and herbal medicines. Screening of retrieved preclinical studies revealed 30 traditional herbal medicines: 8 single herbs, 15 bioactive constituents, and 7 herbal formulas. The antidepressant-like effects of these medicines were associated with reversal of chronic stress-induced impairment in neuroplasticity, most notably by BDNF up-regulation, activation of BDNF downstream signaling pathways and increase in neurogenesis in the hippocampus and/or PFC/frontal cortex. In light of the ability of these medicines to enhance neuroplasticity, we suggest that they may be suitable candidates for clinical investigation in depressed individuals. Once their efficacy, tolerability and safety will be substantiated, they may serve as natural alternatives to conventional antidepressants.

Neuroplasticity-related mechanisms underlying the antidepressant-like effects of traditional herbal medicines.

Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.

Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression.

Posttraumatic stress disorder (PTSD) is a debilitating condition highly comorbid with depression. The endocannabinoid (eCB) system and brain-derived neurotrophic factor (BDNF) are suggestively involved in both disorders. We examined whether cannabinoids can prevent the long-term depressive-like symptoms induced by exposure to the shock and situational reminders (SRs) model of PTSD. The CB1/2 receptor agonist WIN55,212-2 (0.5 mg/kg; i.p.), the fatty acid hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg, i.p.) or vehicle were administered 2 h after severe shock. Cannabinoids prevented the shock/SRs-induced alterations in social recognition memory, locomotion, passive coping, anxiety-like behavior, anhedonia, fear retrieval, fear extinction and startle response as well as the decrease in BDNF levels in the hippocampus and prefrontal cortex (PFC). Furthermore, significant correlations were found between depressive-like behaviors and BDNF levels in the brain. The findings suggest that cannabinoids may prevent both depressive- and PTSD-like symptoms following exposure to severe stress and that alterations in BDNF levels in the brains' fear circuit are involved in these effects.

Cannabinoids prevent depressive-like symptoms and alterations in BDNF expression in a rat model of PTSD.

Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT's mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT's anxiolytic-like effect is exerted by alterations in GABA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABA receptor levels were analyzed using [H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.

Ravid Doron

School of Behavioral Sciences

Academic College of Tel Aviv-Yaffo

The Forced Swim Test as a Model of Depressive-like Behavior

The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice

Ravid Doron

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}School of Behavioral Sciences

Academic College of Tel Aviv-Yaffo

The Forced Swim Test as a Model of Depressive-like Behavior

The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice

School of Behavioral Sciences