Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus

Inserm U-661, Montpellier, France.
PLoS ONE (Impact Factor: 3.53). 02/2010; 5(2):e9159. DOI: 10.1371/journal.pone.0009159
Source: PubMed

ABSTRACT 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.
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.
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.

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Available from: Fontanaud Pierre, Jul 29, 2015
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    • "The demonstration that the ghrelin-induced increase in GHRH neuron excitability is, at least in part, a consequence of a ghrelin-induced decrease in GABAergic transmission efficacy onto GHRH neurons, without affecting glutamate inputs, matches previous similar observations on inhibitory postsynaptic spontaneous currents or potentials in other neuronal cell types such as dopaminergic neurons of the ventral tegmental area (Abizaid et al., 2006) or hypothalamic paraventricular neurons (Mladenov et al., 2006). Analysing the global GABAergic neuronal network, Osterstock et al. (2010) concluded that 'ghrelin does not modify synaptic currents of GHRH neurons'. In contrast, when measuring electrically-evoked monosynaptic "
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