Elsevier

Neuroscience

Volume 161, Issue 3, 7 July 2009, Pages 855-864
Neuroscience

Neuropharmacology
Research Paper
Peripherally administered ghrelin induces bimodal effects on the mesolimbic dopamine system depending on food-consumptive states

https://doi.org/10.1016/j.neuroscience.2009.03.086Get rights and content

Abstract

Ghrelin induces orexigenic behavior by activation of growth hormone secretagogue 1 receptors (GHSRs) in the ventral tegmental area (VTA) as well as hypothalamus, suggesting the involvement of mesolimbic dopamine system in the action of ghrelin. The present study aimed to identify neuronal mechanisms by which peripherally administered ghrelin regulates the mesolimbic dopamine system under different food-consumptive states. Ghrelin was administered to rats peripherally (3 nmol, i.v.) as well as locally into the VTA (0.3 nmol). Dopamine in the nucleus accumbens shell (NAc) was measured by microdialysis. Peripheral administration of ghrelin decreased dopamine levels in the NAc when food was removed following ghrelin administration. This inhibitory effect was mediated through GABAA and N-methyl-d-aspartate (NMDA) receptors in the VTA. In contrast, when animals consumed food following ghrelin administration, dopamine levels increased robustly. This stimulatory effect was mediated through NMDA receptors, but not through GABAA receptors, in the VTA. Importantly, both the inhibitory and stimulatory effects of ghrelin primarily required activation of GHSRs in the VTA. Furthermore, local injection of ghrelin into the VTA induced dopamine release in the NAc and food consumption, supporting the local action of ghrelin in the VTA. In conclusion, peripherally administered ghrelin activates GHSRs in the VTA, and induces bimodal effects on mesolimbic dopamine neurotransmission depending on food-consumptive states.

Section snippets

Animals

Male Wistar rats (270–340 g, Kyudo, Tosu, Japan) were used. The rats were maintained at 23±2 °C under a 12-h light/dark cycle with free access to food and water. Two rats were housed in one home cage till the surgery. All rats used in this study were handled in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Institutes of Health, and the specific protocols were approved by the Committee for Animal Experimentation, Kurume

Effect of peripherally administered ghrelin followed by food removal on the dialysate content of dopamine in the NAc

I.v. administration of ghrelin (3 nmol/0.2 mL) in the absence of food reduced the extracellular dopamine levels in the NAc to about 60% of basal levels (Fig. 1A). The statistically significant decrease lasted for 1 h after ghrelin administration (F9,45=4.01, P<0.0001). The animals displayed walking and rearing for a short period after ghrelin administration and maintained the sleeping position throughout the course of the experiment. In control rats received i.v. administration of saline (0.2

Discussion

The present study demonstrates that peripherally administered ghrelin affects the mesolimbic dopamine system differentially depending on the state of food consumption. Under conditions without food consumption, ghrelin inhibits dopamine neurons in the VTA and dopamine release in the NAc. The inhibitory effect of ghrelin is mediated through interactive actions of GHSRs, NMDA receptors and GABAA receptors in the VTA. In contrast, under conditions with food consumption, ghrelin stimulated dopamine

Acknowledgments

This work was supported by the Kurume University School of Medicine and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (19592308 and 18300128). We wish to thank Professor Masayasu Kojima for his comments and Professor Tatsuyuki Kakuma for advice on the statistical analysis.

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