Increasing evidence has demonstrated that emotional states and intestinal conditions are inter-connected in so-called “brain–gut interactions.” Indeed, many psychiatric disorders are accompanied by ...gastrointestinal symptoms, such as the irritable bowel syndrome (IBS). However, the functional connection remains elusive, partly because there are few useful experimental animal models. Here, we focused on a highly validated animal model of stress-induced psychiatric disorders, such as depression, known as the chronic vicarious social defeat stress (cVSDS) model mice, which we prepared using exposure to repeated psychological stress, thereafter examining their intestinal conditions. In the charcoal meal test and the capsaicin-induced hyperalgesia test, cVSDS model mice showed a significantly higher intestinal transit ratio and increased visceral pain-related behaviors, respectively. These changes persisted over one month after the stress session. On the other hand, the pathological evaluations of the histological and inflammatory scores of naive and cVSDS model mice did not differ. Furthermore, keishikashakuyakuto—a kampo medicine clinically used for the treatment of IBS—normalized the intestinal motility change in cVSDS model mice. Our results indicate that cVSDS model mice present IBS-like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesion. We therefore propose the cVSDS paradigm as a novel animal model of IBS with wide validity, elucidating the correlation between depressive states and intestinal abnormalities.
Disulfiram is an FDA approved drug for the treatment of alcoholism. The drug acts by inhibiting aldehyde dehydrogenase, an enzyme essential to alcohol metabolism. However, a recent study has ...demonstrated that disulfiram also potently inhibits the cytoplasmic protein FROUNT, a common regulator of chemokine receptor CCR2 and CCR5 signaling. Several studies have reported that chemokine receptors are associated with the regulation of emotional behaviors in rodents, such as anxiety. Therefore, this study was performed to clarify the effect of disulfiram on emotional behavior in rodents. The anxiolytic-like effects of disulfiram were investigated using an elevated plus-maze (EPM) test, a typical screening model for anxiolytics. Disulfiram (40 or 80 mg/kg) significantly increased the amount of time spent in the open arms of the maze and the number of open arm entries without affecting the total open arms entries. Similar results were obtained in mice treated with a selective FROUNT inhibitor, disulfiram-41 (10 mg/kg). These disulfiram-associated behavioral changes were similar to those observed following treatment with the benzodiazepine anxiolytic diazepam (1.5 mg/kg). Moreover, disulfiram (40 mg/kg) significantly and completely attenuated increased extracellular glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) during stress exposure on the elevated open-platform. However, no effect in the EPM test was seen following administration of the selective aldehyde dehydrogenase inhibitor cyanamide (40 mg/kg). In contrast to diazepam, disulfiram caused no sedation effects in the open-field, coordination disorder on a rotarod, or amnesia in a Y-maze. This is the first report suggesting that disulfiram produces anxiolytic-like effects in rodents. We found that the presynaptic inhibitory effects on glutaminergic neurons in the PL-PFC may be involved in its underlying mechanism. Disulfiram could therefore be an effective and novel anxiolytic drug that does not produce benzodiazepine-related adverse effects, such as amnesia, coordination disorder, or sedation, as found with diazepam. We propose that the inhibitory activity of disulfiram against FROUNT function provides an effective therapeutic option in anxiety.
Recently, we developed that the mice chronic vicarious social defeat stress (cVSDS) model, known as validated animal model of depression, showed the irritable bowel syndrome (IBS)-like symptoms such ...as chronic intestinal motility changes and abdominal hyperalgesia without organic lesions. Previously, we reported that a selective delta opioid receptor (DOP) agonist KNT-127 improved the depression-like behaviors observed in mice cVSDS model. In the present study, we examined the effects of KNT-127 on the IBS-like symptoms in cVSDS model. The model mice were prepared by exposure to repeated psychological stress for 10 days in C57BL/6J mice. KNT-127 was administered subcutaneously (s.c.) and microinjected into the Insular cortex (IC) 30min before the test, respectively. KNT-127 (10mg/kg, s.c.) significantly improved increased intestinal transit ratio in the charcoal meal test and hypersensitivity symptoms in the capsaicin-induced hyperalgesia test, respectively. In addition, KNT-127 (300ng/mouse) in IC was normalized their intestinal transit ratio. These results suggested that KNT-127 improved the IBS-like symptoms in cVSDS mice via DOPs in IC. We proposed that DOP agonist have the potential to be an effective treatment for IBS, capable of breaking the vicious cycle in gut-brain interactions.
Recently, we developed that the mice chronic vicarious social defeat stress (cVSDS) model, known as validated animal model of depression, showed the irritable bowel syndrome (IBS)-like symptoms such ...as chronic intestinal motility changes and abdominal hyperalgesia without organic lesions. Previously, we reported that a selective delta opioid receptor (DOP) agonist KNT-127 improved the depression-like behaviors observed in mice cVSDS model. In the present study, we examined the effects of KNT-127 on the IBS-like symptoms in cVSDS model. The model mice were prepared by exposure to repeated psychological stress for 10 days in C57BL/6J mice. KNT-127 was administered subcutaneously (s.c.) and microinjected into the Insular cortex (IC) 30min before the test, respectively. KNT-127 (10mg/kg, s.c.) significantly improved increased intestinal transit ratio in the charcoal meal test and hypersensitivity symptoms in the capsaicin-induced hyperalgesia test, respectively. In addition, KNT-127 (300ng/mouse) in IC was normalized their intestinal transit ratio. These results suggested that KNT-127 improved the IBS-like symptoms in cVSDS mice via DOPs in IC. We proposed that DOP agonist have the potential to be an effective treatment for IBS, capable of breaking the vicious cycle in gut-brain interactions.
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