Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus.
BACKGROUND
Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin.


RESULTS
Here, we show that ghrelin stimulates the firing rate of identified GHRH neurons, in transgenic GHRH-GFP mice. This stimulation is prevented by growth hormone secretagogue receptor-1 antagonism as well as by U-73122, a phospholipase C inhibitor and by calcium channels blockers. The effect of ghrelin does not require synaptic transmission, as it is not antagonized by gamma-aminobutyric acid, glutamate and NPY receptor antagonists. In addition, this hypothalamic effect of ghrelin is independent of somatostatin, the inhibitor of the GH axis, since it is also found in somatostatin knockout mice. Indeed, ghrelin does not modify synaptic currents of GHRH neurons. However, ghrelin exerts a strong and direct depolarizing effect on GHRH neurons, which supports their increased firing rate.


CONCLUSIONS
Thus, GHRH neurons are a specific target for ghrelin within the brain, and not activated secondary to altered activity in feeding circuits. These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.
Osterstock
Guillaume
G
Inserm U-661, Montpellier, France.
Escobar
Pauline
P
Mitutsova
Violeta
V
Gouty-Colomer
Laurie-Anne
LA
Fontanaud
Pierre
P
Molino
François
F
Fehrentz
Jean-Alain
JA
Carmignac
Danielle
D
Martinez
Jean
J
Guerineau
Nathalie C
NC
Robinson
Iain C A F
IC
Mollard
Patrice
P
Méry
Pierre-François
PF
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D054439:Ghrelin / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D007211:Indoles; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011760:Pyrrolidinones / Q000494:pharmacology; D054440:Receptors, Ghrelin / Q000819:agonists; D014364:Tryptophan / Q000031:analogs & derivatives; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004963:Estrenes; D054439:Ghrelin; D007211:Indoles; D009842:Oligopeptides; D011760:Pyrrolidinones; D054440:Receptors, Ghrelin; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D049452:Green Fluorescent Proteins; C041048:growth hormone releasing hexapeptide; C582727:macimorelin; D014364:Tryptophan; D013007:Growth Hormone-Releasing Hormone; D010738:Type C Phospholipases