Abstract
Several severe stressful situations, e.g., natural disaster, infectious disease out break, and mass casualty, are known to cause anxiety, depression and cognitive impairment, and preventive intervention for these stress complications is worth exploring. We have previously reported that the serotonin-norepinephrine-dopamine reuptake inhibitor, venlafaxine, as well as voluntary wheel running are effective in the treatment of anxiety- and depression-like behaviors in stressed rats. But whether they are able to prevent deleterious consequences of restraint stress in rats, such as anxiety/depression-like behaviors and memory impairment that occur afterward, was not known. Herein, male Wistar rats were pre-treated for 4 weeks with anti-anxiety/anti-depressive drugs, agomelatine and venlafaxine, or voluntary wheel running, followed by 4 weeks of restraint-induced stress. During the stress period, rats received neither drug nor exercise intervention. Our results showed that restraint stress induced mixed anxiety- and depression-like behaviors, and memory impairment as determined by elevated plus-maze, elevated T-maze, open field test (OFT), forced swimming test (FST), and Morris water maze (MWM). Both pharmacological pre-treatments and running successfully prevented the anxiety-like behavior, especially learned fear, in stressed rats. MWM test suggested that agomelatine, venlafaxine, and running could prevent stress-induced memory impairment, but only pharmacological treatments led to better novel object recognition behavior and positive outcome in FST. Moreover, western blot analysis demonstrated that venlafaxine and running exercise upregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. In conclusion, agomelatine, venlafaxine as well as voluntary wheel running had beneficial effects, i.e., preventing the restraint stress-induced anxiety/depression-like behaviors and memory impairment.
Highlights
Stress can cause psychiatric disorders, disability and mortality
Since stress hormone glucocorticoids can induce the release of several neurotransmitters, e.g., serotonin, norepinephrine, and dopamine [1], mood disorders are often intractable to conventional pharmacological treatments that target single neurotransmitter, such as benzodiazepines and fluoxetine [2]
Hypothalamic glucocorticoid receptor (GR) protein expression was significantly higher in 1-week stressed rats than that of the control rats [t(8) = 3.990, p = 0.002] (Fig 1H), indicating hyperactivity of HPA axis
Summary
Since stress hormone glucocorticoids can induce the release of several neurotransmitters, e.g., serotonin, norepinephrine, and dopamine [1], mood disorders are often intractable to conventional pharmacological treatments that target single neurotransmitter, such as benzodiazepines and fluoxetine [2]. The serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) venlafaxine has been reported to increase monoamine levels in several brain regions related to anxiety, depression, and memory [6, 7]. Our recent investigation demonstrated that the serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI), venlafaxine, and voluntary wheel running effectively alleviated anxiety- and depression-like behaviors in stressed male rats [8, 9]. Besides venlafaxine, agomelatine, the melatonin MT1 and MT2 receptor agonist and 5-HT2C receptor antagonist with robust anxiolytic and antidepressant effects in humans, rats, and mice [10,11,12], could be a candidate drug for the preventing stress-induced behavioral change
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