A Role of Ghrelin in Neuroendocrine and Behavioral Responses to Stress in Mice

Asakawa, Akihiro; Inui, Akio; Kaga, Toshihiro; Yuzuriha, H; Nagata, Toshiaki; Fujimiya, Mineko; Katsuura, Goro; Makino, Susumu; Fujino, Masayuki; Kasuga, Masato

doi:10.1159/000054680

Cited by 353 publications

(294 citation statements)

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“…2a). This finding is consistent with previous studies that have demonstrated increases in gastric ghrelin mRNA or total plasma ghrelin after acute stress 5,6 .…”

Section: Online)supporting

confidence: 94%

The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress

et al. 2008

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We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic-and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.Chronic stress induces changes in mood, feeding and metabolism by a poorly understood neurobiological mechanism. Recent studies have suggested that key metabolic signals may interact with CNS circuits to regulate reward and mood 1 . To further explore these links, we investigated the potential role of ghrelin, an important feeding peptide, in the development of depressive symptoms. Ghrelin is a hormone synthesized predominantly by specialized gastrointestinal endocrine cells and is released during periods of negative energy balance 2 . In response to energy insufficiency, ghrelin induces a potent feeding response via activation of the growth hormone secretagogue receptor (GHSR, ghrelin receptor) 2,3 .To determine whether ghrelin can affect mood symptoms, we physiologically increased ghrelin levels by restricting the food intake of mice with a diet containing 60% of normal calories for Fig. 1). This resulted in a fourfold increase in circulating levels of acylated ghrelin (calorie restricted wild-type mice: 7.93 ± 1.59 pg mL −1 , n = 6; wildtype mice fed ad libitum: 1.98 ± 0.37 pg mL −1 , n = 5; P < 0.01). Calorie-restricted wild-type mice showed robust anxiolytic-and antidepressant-like behavior in the elevated plus maze (EPM) and forced swim test (FST), respectively, as compared with wild-type mice fed ad libitum (controls; Fig. 1a,c). In contrast, genetic blockade of ghrelin signaling in Ghsr −/− mice negated these calorie restriction-associated anxiolytic-and antidepressant-like effects. Further analyses demonstrated that the observed differences between the two genotypes cannot be attributed to differences in sensorimotor coordination, general locomotor activity or body weight ( Supplementary Figs. 1-3 online).We used a pharmacologic approach to extend our food-restriction results. We subcutaneously injected C57BL6/J mice with a dose of ghrelin that induces potent feeding (Fig. 1f) and tested them in the EPM and FST 45 min later. Mice receiving ghrelin demonstrated significantly less anxiety-and depression-like symptoms in these tests compared with saline-injected controls (Fig. 1b,d).Next, we determined whether ghrelin signaling regulates depressive symptoms in a mouse model of chronic stress. We used the chronic social defeat stress (CSDS) procedure, which subjects mice to ten daily bouts of social defeat by aggressive CD1 male mice 1,4 (Fig. 2). Mice subjected to CSDS showed lasting behavioral deficits, including social avoidance ( Suppl...

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“…2a). This finding is consistent with previous studies that have demonstrated increases in gastric ghrelin mRNA or total plasma ghrelin after acute stress 5,6 .…”

Section: Online)supporting

confidence: 94%

The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress

et al. 2008

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“…Ghrelin stimulates the HPA axis via stimulation of CRH release from the hypothalamus. Blockade of CRF receptors has been shown to attenuate ghrelin-induced anxiogenesis in the elevated plus maze test (Asakawa et al, 2001a), and injection of astressin (CRF2 receptor antagonist) attenuated ghrelin-induced plasma corticosterone increase in neonatal chicks (Saito et al, 2005). We have demonstrated that CRF, like ethanol, augments GABAergic transmission, and that ethanol dependence heightens the sensitivity to CRF and CRF 1 antagonists in CeA (Roberto et al, 2010).…”

Section: Discussionmentioning

confidence: 69%

“…In mice, peripheral and central administration of ghrelin reduced the total number of entries and total time spent in the open arms in an elevated plus maze test (Asakawa et al, 2001a). Furthermore, starvation stress increased ghrelin gene expression (Asakawa et al, 2001b) and tail pinch stress significantly increased ghrelin mRNA expression (Asakawa et al, 2001a).…”

Section: Discussionmentioning

confidence: 97%

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Cruz

Herman

Cote

et al. 2012

Neuropsychopharmacol

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The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists D-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. D-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, D-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses.

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“…Ghrelin levels are reported to be decreased in obesity (13) and increase after diet-induced weight loss (14). Preliminary data in rodents suggest that ghrelin can also affect neuroendocrine and behavioral responses to stress (15).…”

mentioning

confidence: 99%

Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity

Yildiz

Suchard

Wong

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

322

219

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Ghrelin plays a key role in the regulation of growth hormone secretion and energy homeostasis. Adiponectin is exclusively secreted by adipose tissue and is abundantly present in the circulation, with important effects on metabolism. We studied five lean and five obese young men [ages: 24.2 ؎ 1.0 (lean) and 21.8 ؎ 1.6 (obese) years (difference not significant); body mass indexes: 35.0 ؎ 1.3 and 23.0 ؎ 0.3 kg͞m 2 (P ‫؍‬ 0.01)], sampled blood every 7 min over 24 h, and measured ghrelin, adiponectin, and leptin in 2,070 samples for a total of 6,210 data points. Circulating 24-h ghrelin showed significant ultradian fluctuations and an orderly pattern of release in lean and obese subjects with similar pulsatility characteristics. Plasma adiponectin concentrations were significantly lower in the obese group, with lower pulse height. In contrast to leptin, which is secreted in an orderly manner, the 24-h patterns of adiponectin were not significantly different from random in both the lean and obese groups. We show here that adipocytes can simultaneously secrete certain hormones, such as leptin, in patterns that are orderly, whereas other hormones, such as adiponectin, are secreted in patterns that appear to be random. The cross-approximate entropy statistic revealed pattern synchrony among ghrelin-leptin, ghrelin-adiponectin, and leptinadiponectin hormone time series in the lean and obese subjects. Plasma ghrelin concentrations showed a nocturnal rise that exceeded the meal-associated increases in lean subjects, and this newly identified nocturnal rise was blunted in the obese. We suggest that the blunting of the nocturnal rise of ghrelin is a biological feature of human obesity.

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A Role of Ghrelin in Neuroendocrine and Behavioral Responses to Stress in Mice

Cited by 353 publications

References 15 publications

The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress

The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity

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