Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite.
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.
Abizaid
Alfonso
A
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06519, USA.
Liu
Zhong-Wu
ZW
Andrews
Zane B
ZB
Shanabrough
Marya
M
Borok
Erzsebet
E
Elsworth
John D
JD
Roth
Robert H
RH
Sleeman
Mark W
MW
Picciotto
Marina R
MR
Tschöp
Matthias H
MH
Gao
Xiao-Bing
XB
Horvath
Tamas L
TL
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001066:Appetite / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D005455:Fluorescent Antibody Technique / Q000379:methods; D054439:Ghrelin; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D054440:Receptors, Ghrelin; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D054439:Ghrelin; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D004298:Dopamine