Ghrelin Receptor Influence on Cocaine Reward is Not Directly Dependent on Peripheral Acyl-Ghrelin

The peptide hormone acyl-ghrelin and its receptor, GHSR_1a, 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 GHSR_1a. Overall, these data indicate that GHSR_1a 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 GHSR_1a populations is used to generate a regulatory model for functional manipulation of specific effects when attempting to therapeutically target the ghrelin system.