Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight homeostasis. For instance, ghrelin levels rise in association with hunger and fasting. Also, ghrelin stimulates food intake, decreases energy expenditure, and induces obesity when present in high concentrations. Ghrelin's actions are mediated by interaction with its receptor, the growth hormone secretagogue receptor (GHSR;ghrelin receptor), which has a well-defined, discrete pattern of expression within the brain. This includes a high degree of expression in dopamine-containing neurons within a part of the brain known as the ventral tegmental area (VTA). These dopaminergic VTA neurons have been highly studied due to their involvement in brain reward circuits, such as those associated with addiction. The current application provides a series of studies designed to increase our understanding of the involvement of ghrelin in promoting reward- seeking behaviors and the role of the VTA in ghrelin action. In particular, the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and cocaine will be investigated. To accomplish this, unique mouse models in which either expression of the ghrelin receptor has been deleted or the functioning of the ghrelin receptor has been blocked by the administration of a specific antagonist will be used. These mice will be subjected to a battery of tests that will allow us to determine the effect of genetic and pharmacological blockade of ghrelin signaling pathways on food-reinforced and cocaine-reinforced reward-seeking behaviors. Also, a unique mouse model in which ghrelin receptor expression can be selectively targeted to dopaminergic VTA neurons will be used in order to investigate the sufficiency of ghrelin's engagement of these particular neurons for its actions on reward behaviors and body weight. This selective targeting will involve state-of-the- art neuroanatomical and transgenic techniques. It is hoped that these studies will result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction. PUBLIC HEALTH RELVANCE The experiments proposed in this study have been designed to investigate the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and addictive drugs such as cocaine. It is hoped that these studies will eventually result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024680-05
Application #
8261735
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2008-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$299,614
Indirect Cost
$107,554
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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