Cocaine- and amphetamine-regulated transcript mediates the actions of cholecystokinin on rat vagal afferent neurons.
OBJECTIVE
Cholecystokinin (CCK) acts on vagal afferent neurons to inhibit food intake and gastric emptying; it also increases expression of the neuropeptide cocaine- and amphetamine-regulated transcript (CART), but the significance of this is unknown. We investigated the role of CARTp in vagal afferent neurons.


METHODS
Release of CART peptide (CARTp) from cultured vagal afferent neurons was determined by enzyme-linked immunosorbent assay. Expression of receptors and neuropeptides in rat vagal afferent neurons in response to CARTp was studied using immunohistochemistry and luciferase promoter reporter constructs. Effects of CARTp and CCK were studied on food intake.


RESULTS
CCK stimulated CARTp release from cultured nodose neurons. CARTp replicated the effect of CCK in stimulating expression of Y2R and of CART itself in these neurons in vivo and in vitro, but not in inhibiting cannabinoid-1, melanin-concentrating hormone, and melanin-concentrating hormone-1 receptor expression. Effects of CCK on Y2R and CART expression were reduced by CART small interfering RNA or brefeldin A. Exposure of rats to CARTp increased the inhibitory action of CCK on food intake after short-, but not long-duration, fasting.


CONCLUSIONS
The actions of CCK in stimulating CART and Y2R expression in vagal afferent neurons and in inhibiting food intake are augmented by CARTp; CARTp is released by CCK from these neurons, indicating that it acts as an autocrine excitatory mediator.
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, UK.
Guillaume
G
De Lartigue
Rod
R
Dimaline
Andrea
A
Varro
Helen
H
Raybould
Claire Barbier
CB
De la Serre
Graham J
GJ
Dockray
D000818:Animals; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000494:pharmacology*; D007028:Hypothalamic Hormones / Q000235:genetics; D008297:Male; D008543:Melanins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects*; D009620:Nodose Ganglion / Q000187:drug effects; D010907:Pituitary Hormones / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000235:genetics; D014630:Vagus Nerve / Q000187:drug effects*; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D007028:Hypothalamic Hormones; D008543:Melanins; D009419:Nerve Tissue Proteins; D010907:Pituitary Hormones; D017476:Receptors, Neuropeptide Y; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; C095889:neuropeptide Y2 receptor; C019463:melanin-concentrating hormone; D002766:Cholecystokinin