Serotonin 2C receptor antagonism ameliorates novelty-induced hypophagia in aged mice

Nahata, Miwa; Muto, Shuichi; Nakagawa, Koji; Ohnishi, Shunsuke; Sadakane, Chiharu; Saegusa, Yayoi; Iizuka, Seiichi; Hattori, Tomohisa; Asaka, Masahiro; Takeda, Hiroshi

doi:10.1016/j.psyneuen.2013.03.014

Cited by 22 publications

(58 citation statements)

References 42 publications

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“…The effect of rikkunshito on GE was blocked by the co‐administration of ghrelin receptor antagonist, and supplementation of exogenous acylated ghrelin augmented GE, which is mediated by vagal nerve activity in the brain‐gut axis. Several studies have suggested that the oral administration of rikkunshito acts on the central nervous system . However, decreased peripheral ghrelin levels in the UCN1‐induced stress model have been reported that involve the stimulation of peripheral, rather than central α 2 ‐AR .…”

Section: Discussionmentioning

confidence: 99%

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model

Harada

Ochiai

et al. 2015

Neurogastroenterology Motil

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BackgroundFunctional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal‐enhancing action for FD treatment.MethodsSolid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) ‐induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, rikkunshito, or an α 2‐adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free‐moving condition.Key ResultsExogenous acylated ghrelin supplementation restored UCN1‐induced delayed GE. Alpha2‐AR antagonist and rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of rikkunshito on delayed GE was blocked by co‐administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or rikkunshito.Conclusions & InferencesThe UCN1‐induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by rikkunshito may be effective in treating functional GI disorders.

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Section: Discussionmentioning

confidence: 99%

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model

Harada

Ochiai

et al. 2015

Neurogastroenterology Motil

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“…Testing was performed as previously described13. Group-housed mice (five mice per cage) were suddenly transferred to separate cages (one mouse per cage) after overnight fasting.…”

Section: Methodsmentioning

confidence: 99%

“…The administered dose of RKT is approximately equivalent to a typical clinical dose when converted based on body surface area (as recommended by the FDA) and this dose has previously been reported to show ameliorative effects in a mouse model of anorexia13144041. Cumulative food intake was determined at 1, 3 and 6 h after stress exposure.…”

Section: Methodsmentioning

confidence: 99%

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

Mogami

Sadakane

Nahata

et al. 2016

Sci Rep

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Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities.

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“…These behaviors correspond to those obtained when manipulating the 5-HT 2C receptor with previously described ligands. In tests of depression, antidepression-like behaviors were seen with administration of 5-HT 2C antagonists (Dekeyne et al 2008; Nahata et al 2013), data suggesting that blocking the 5-HT 2C receptor induces these antidepression-like behaviors. In terms of anxiety-like behaviors, more anatomical specific data is known.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological manipulation of this receptor can modulate depression and anxiety-like behaviors in animal models. In both mice and rats, antagonists for 5-HT 2C tend to decrease depression-like behaviors (Dekeyne et al 2008; Nahata et al 2013). Changes in anxiety-like behaviors tend to occur with activation of 5-HT 2C receptors in the basolateral amygdala (BLA), dorsal periaqueductal gray (PAG) or ventral hippocampus (Campbell & Merchant 2003; Alves et al 2004; Overstreet et al 2006; Gomes & Nunes-De-Souza 2009; Yamashita et al 2011; Pockros-Burgess et al 2014; Vicente & Zangrossi 2014).…”

Section: Introductionmentioning

confidence: 99%

Marine cyanobacteria-derived serotonin receptor 2C active fraction induces psychoactive behavioral effects in mice

Lax

Ahmed

Ignatz

et al. 2016

Pharmaceutical Biology

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Context Marine cyanobacteria offer a robust resource for natural products drug discovery due to the secondary metabolites they produce. Objective To identify novel cyanobacterial compounds that exhibit CNS psychoactive effects. Materials and methods Cyanobacteria were collected from Las Perlas Archipelago, Panama and subjected to dichloromethane/methanol extraction and fractionation by column chromatography before being screened for affinity against a panel of CNS targets. A 50:50 ethyl acetate:methanol fraction of one cyanobacterial extract (2064H) was subjected to HPLC and the major peak was isolated (2064H3). At a dose of 20 μg per animal, 2064H and 2064H3 were tested in mice using behavioral assays that included the forced swim, open field, and formalin tests. Results 2064H was shown to bind to the serotonin 2C (5-HT2C) receptor, a known target for depression and pain treatment. 2064H showed 59.6% inhibition of binding of [3H]-mesulergine with an IC50 of 179 ng/mL and did not show inhibition of binding greater than 45% with any other receptors tested. Both 2064H and 2064H3 decreased immobility time in the first min of the tail suspension test. 2064H increased time, distance and number of entries in the center region in the first half of the open field test. 2064H increased overall nocifensive behaviors in the formalin test. Discussion and Conclusion Overall, manipulating the 5-HT2C receptor with these receptor-specific ligands derived from cyanobacteria altered pain, depression and anxiety-like behaviors, illustrating the importance of this receptor in affective behaviors. These results demonstrate the potential of cyanobacteria as a source for CNS active compounds.

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Serotonin 2C receptor antagonism ameliorates novelty-induced hypophagia in aged mice

Cited by 22 publications

References 42 publications

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

Marine cyanobacteria-derived serotonin receptor 2C active fraction induces psychoactive behavioral effects in mice

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