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Abstract
The peptide hormone acyl-ghrelin and its receptor, GHSR1a, represent intriguing therapeutic targets due to their actions in metabolic homeostasis and reward activity. However, this pleotropic activity makes it difficult to intervene in this system without inducing unwanted effects. Thus, it is desirable to identify passive and active regulatory mechanisms that allow differentiation between functional domains. Anatomical restriction by the blood brain barrier represents one major passive regulatory mechanism. However, it is likely that the ghrelin system is subject to additional passive mechanisms that promote independent regulation of orexigenic behavior and reward processing. By applying acyl-ghrelin sequestering antibodies, it was determined that peripheral sequestration of acyl-ghrelin is sufficient to blunt weight gain, but not cocaine rewarding effects. However, both weight gain and reward-associated behaviors were shown to be blocked by direct antagonism of GHSR1a. Overall, these data indicate that GHSR1a effects on reward are independent from peripheral acyl-ghrelin binding, whereas centrally-mediated alteration of energy storage requires peripheral acyl-ghrelin binding. This demonstration of variable ligand-dependence amongst functionally-distinct GHSR1a populations is used to generate a regulatory model for functional manipulation of specific effects when attempting to therapeutically target the ghrelin system.
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1 The Scripps Research Institute, Department of Chemistry, La Jolla, USA (GRID:grid.214007.0) (ISNI:0000000122199231); University of Wisconsin – Madison, Department of Pharmacy, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675)
2 The Scripps Research Institute, Department of Chemistry, La Jolla, USA (GRID:grid.214007.0) (ISNI:0000000122199231)
3 National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Neurobiology of Addiction Section, Baltimore, USA (GRID:grid.420090.f) (ISNI:0000 0004 0533 7147)
4 National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); Brown University, Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094)
5 The Scripps Research Institute, Department of Chemistry, La Jolla, USA (GRID:grid.214007.0) (ISNI:0000000122199231); The Skaggs Institute for Chemical Biology, and The Worm Institute for Research and Medicine (WIRM), The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, USA (GRID:grid.214007.0) (ISNI:0000000122199231)