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Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite
Alfonso Abizaid, … , Xiao-Bing Gao, Tamas L. Horvath
Alfonso Abizaid, … , Xiao-Bing Gao, Tamas L. Horvath
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3229-3239. https://doi.org/10.1172/JCI29867.
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Research Article Metabolism Article has an altmetric score of 12

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

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Abstract

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.

Authors

Alfonso Abizaid, Zhong-Wu Liu, Zane B. Andrews, Marya Shanabrough, Erzsebet Borok, John D. Elsworth, Robert H. Roth, Mark W. Sleeman, Marina R. Picciotto, Matthias H. Tschöp, Xiao-Bing Gao, Tamas L. Horvath

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Figure 2

Ghrelin increases action potential generation in VTA DA neurons in mice (n = 9) and rats (n = 6).

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Ghrelin increases action potential generation in VTA DA neurons in mice ...
(A) Raw traces recorded before (Control), during (Ghrelin), and after (Washout) application of ghrelin. (B) Time course of the ghrelin-induced increase in frequency of action potential (FAP). A–C represent time points when traces from A were recorded. (C and D) Mean frequency of action potentials recorded in mice (C) and rats (D) before, during, and after application of ghrelin. Hyperpolarization-induced action current recorded from DA neurons is shown (D, inset). (E and F) Ghrelin-mediated enhancement of action potential generation in VTA DA neurons required excitatory inputs. Shown are mean frequency of action potentials recorded before, during, and after application of ghrelin. (E) No effect of ghrelin was observed on frequency of action potentials in slices from GHSR-knockout mice (n = 5). (F) In the absence of excitatory input onto DA neurons, no effect of ghrelin was observed on frequency of action potentials in slices from wild-type mice (n = 6) in the presence of CNQX (10 μM) and AP5 (50 μM) in all solutions. Results were pooled from all recorded neurons. (G) Experiments were performed in slices from wild-type mice (n = 7) in the presence of bicuculline (30 μM) in all solutions. Results were pooled from all recorded neurons. In the absence of inhibitory inputs of DA neurons, ghrelin elevated the frequency of action potentials of VTA DA neurons, an effect that diminished after washout.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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