Background
Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation,
and recent evidence suggests ghrelin prevents excessive anxiety under conditions of
chronic stress.
Methods
We used ghrelin knockout (ghr−/−) mice to examine the role of endogenous ghrelin in
anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute
stress.
Results
Ghr−/− mice are more anxious after acute restraint stress, compared with wild-type
(WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated
neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus
of the amygdala in ghr−/− mice compared with WT, and exogenous ghrelin reversed this
effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal
nucleus in WT but not ghr−/− mice. Ghr−/− mice exhibited a lower corticosterone response
after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence
of ghrelin. We found no differences in dexamethasone-induced Fos expression between
ghr−/− and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic
hormone replacement elevated plasma corticosterone in ghr−/−, compared with WT mice,
indicating increased adrenal sensitivity. The adrenocorticotropic hormone response
to acute stress was significantly reduced in ghr−/− mice, compared with control subjects.
Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue
receptor.
Conclusions
Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level
of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit
involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus
promotes an appropriate stress response. Thus, ghrelin regulates acute stress and
offers potential therapeutic efficacy in human mood and stress disorders.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat.Psychoneuroendocrinology. 2007; 32: 693-702
- Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment.Clin Biochem. 2009; 42: 1076-1081
- The extra-hypothalamic actions of ghrelin on neuronal function.Trends Neurosci. 2010; 93: 48-57
- Ghrelin gene polymorphism is associated with depression, but not panic disorder.Psychiatr Genet. 2008; 18: 257
- Effects of repeated restraint stress on gastric motility in rats.Am J Physiol. 2009; 296: R1358-R1365
- Metabolic signals modulate hypothalamic-pituitary-adrenal axis activation during maternal separation of the neonatal mouse.J Neuroendocrinol. 2006; 18: 865-874
- Hypothalamic-pituitary-adrenal axis activity of newborn mice rapidly desensitizes to repeated maternal absence but becomes highly responsive to novelty.Endocrinology. 2008; 149: 6366-6377
- Acute psychological stress raises plasma ghrelin in the rat.Regul Pept. 2006; 134: 114-117
- A role of ghrelin in neuroendocrine and behavioral responses to stress in mice.Neuroendocrinology. 2001; 74: 143-147
- Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia.J Endocrinology. 2005; 185: 477-484
- The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress.Nat Neurosci. 2008; 11: 752-753
- Ghrelin mediates stress-induced food-reward behavior in mice.J Clin Invest. 2011; 121: 2684-2692
- In vivo characterization of high Basal signaling from the ghrelin receptor.Endocrinology. 2009; 150: 4920-4930
- Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.Proc Nat Acad Sci U S A. 2004; 101: 8227-8232
- Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism.J Neurosci. 2009; 29: 14057-14065
- Early life immune challenge-effects on behavioural indices of adult rat fear and anxiety.Behav Brain Res. 2005; 164: 231-238
- Neonatal overfeeding alters adult anxiety and stress responsiveness.Psychoneuroendocrinology. 2009; 34: 1133-1143
- Anxiety and hypothalamic-pituitary-adrenal axis responses to psychological stress are attenuated in male rats made lean by large litter rearing.Psychoneuroendocrinology. 2011; 36: 1080-1091
- Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety.Prog Neuropsychopharmacol Biol Psyc. 1989; 13: 963-976
- Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: Possible role of the bed nucleus of the stria terminalis.J Comp Neurol. 2005; 481: 363-376
- Postnatal overfeeding leads to obesity and exacerbated febrile responses to lipopolysaccharide throughout life.J Neuroendocrinol. 2012; 24: 511-524
- Analyzing real-time PCR data by the comparative C(T) method.Nat Protoc. 2008; 3: 1101-1108
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.Methods. 2001; 25: 402-408
- Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways.J Neurosci. 2010; 30: 7975-7983
- Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats.Neurobiol Dis. 2009; 36: 343-351
- The grooming analysis algorithm discriminates between different levels of anxiety in rats: potential utility for neurobehavioural stress research.J Neurosci Methods. 2005; 143: 169-177
- Stressor categorization: Acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups.Eur J Neurosci. 2001; 14: 1143-1152
- Neuroendocrine responses to an emotional stressor: Evidence for involvement of the medial but not the central amygdala.Eur J Neurosci. 1999; 11: 2312-2322
- Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin.Biochem Biophys Res Comm. 2004; 313: 635-641
- Expression of ghrelin receptor mRNA in the rat and the mouse brain.J Comp Neurol. 2006; 494: 528-548
- On the role of urocortin 1 in the non-preganglionic Edinger-Westphal nucleus in stress adaptation.Gen Comp Endocrinol. 2007; 153: 235-240
- Ghrelin increases anxiety-like behavior and memory retention in rats.Biochem Biophys Res Comm. 2002; 299: 739-743
- Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress.Stress. 2008; 11: 363-369
- Urocortinergic neurons respond in a differentiated manner to various acute stressors in the Edinger-Westphal nucleus in the rat.J Comp Neurol. 2004; 480: 170-179
- Does midbrain urocortin 1 matter?.Stress. 2011; 14: 376-383
- Spinal and hindbrain structures involved in visceroception and visceronociception as revealed by the expression of Fos, Jun and Krox-24 proteins.Neuroscience. 1993; 55: 737-753
- Neuronal activation in the CNS during different forms of acute renal failure in rats.Neuroscience. 2009; 159: 862-882
- Urocortin expression in the Edinger-Westphal nucleus is up-regulated by stress and corticotropin-releasing hormone deficiency.Endocrinology. 2000; 141: 256-263
- Differential responses of corticotropin-releasing factor and urocortin 1 to acute pain stress in the rat brain.Neuroscience. 2011; 183: 15-24
- The activation of urocortin immunoreactive neurons in the Edinger-Westphal nucelus following acute pain stress in rats.Stress. 2001; 4: 85-90
- Hypophysiotropic neurons of the paraventricular nucleus respond in spatially, temporally, and phenotypically differentiated manners to acute vs. repeated restraint stress: Rapid publication.J Comp Neurol. 2002; 445: 293-307
- The neuro-symphony of stress.Nat Rev Neurosci. 2009; 10: 459-466
- Stress and the brain: from adaptation to disease.Nat Rev Neurosci. 2005; 6: 463-475
- The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology.J Comp Neurol. 2011; 519: 1413-1434
- Effects of mGlu2 or mGlu3 receptor deletions on mGlu2/3 receptor agonist (LY354740)-induced brain c-Fos expression: Specific roles for mGlu2 in the amygdala and subcortical nuclei, and mGlu3 in the hippocampus.Neuropharmacology. 2006; 51: 213-228
- Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions.Neuropsychopharmacology. 2004; 29: 502-513
- Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression.J Neurosci. 2004; 24: 9303-9312
- Distribution of urocortin-like immunoreactivity in the central nervous system of the rat.J Comp Neurol. 1998; 391: 1-10
- Urocortin expression in rat brain: Evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors.J Comp Neurol. 1999; 415: 285-312
- Ghrelin: From a GH-secretagogue to the regulation of food intake, sleep and anxiety.Pediatr Endocrinol Rev. 2004; 1: 432-437
- Relationship between plasma ghrelin levels and insulin resistance and blood pressure in octogenarians.J Huazhong Univ Sci Technolog Med Sci. 2010; 30: 307-311
- Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons.Endocrinology. 2010; 151: 4745-4755
- Ghrelin increases intake of rewarding food in rodents.Addict Biol. 2010; 15: 304-311
- Ghrelin induces adiposity in rodents.Nature. 2000; 407: 908-913
Article info
Publication history
Published online: April 23, 2012
Accepted:
March 5,
2012
Received in revised form:
March 5,
2012
Received:
December 13,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
