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

Abstract

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.

Funding Source

We thank the NIH for support through F32DA043323 (CJW) and Contract HHSN2757015000061 (KDJ). LFV is supported by the NIDA IRP. LL is supported by the NIAAA and NIDA IRPs.

Cited by

This article is cited by 9 publications

Richardson, R. S., Sulima, A., Rice, K. C., Kucharczk, J. A., Janda, K. D., Nisbett, K. E., Koob, G. F., Vendruscolo, L. F., & Leggio, L. (2023). Pharmacological GHSR (ghrelin receptor) blockade reduces alcohol binge-like drinking in male and female mice. Neuropharmacology, 238, 109643. https://doi.org/10.1016/j.neuropharm.2023.109643
Merritt, C. R., Garcia, E. J., Brehm, V. D., Fox, R. G., Moeller, F. G., Anastasio, N. C., & Cunningham, K. A. (2023). Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats. Frontiers in pharmacology, 14, 1268366. https://doi.org/10.3389/fphar.2023.1268366
Jerlhag E. (2023). Animal studies reveal that the ghrelin pathway regulates alcohol-mediated responses. Frontiers in psychiatry, 14, 1050973. https://doi.org/10.3389/fpsyt.2023.1050973
Navarro, G., Rea, W., Quiroz, C., Moreno, E., Gomez, D., Wenthur, C. J., Casadó, V., Leggio, L., Hearing, M. C., & Ferré, S. (2022). Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D1 Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin. The Journal of neuroscience : the official journal of the Society for Neuroscience, 42(6), 940–953. https://doi.org/10.1523/JNEUROSCI.1151-21.2021
Sustkova-Fiserova, M., Charalambous, C., Khryakova, A., Certilina, A., Lapka, M., & Šlamberová, R. (2022). The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions. International journal of molecular sciences, 23(2), 761. https://doi.org/10.3390/ijms23020761
You, Z. B., Galaj, E., Alén, F., Wang, B., Bi, G. H., Moore, A. R., Buck, T., Crissman, M., Pari, S., Xi, Z. X., Leggio, L., Wise, R. A., & Gardner, E. L. (2021). Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 10.1038/s41386-021-01249-2. Advance online publication. https://doi.org/10.1038/s41386-021-01249-2
Shevchouk, O. T., Tufvesson-Alm, M., & Jerlhag, E. (2021). An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side. Frontiers in neuroscience, 15, 774050. https://doi.org/10.3389/fnins.2021.774050
Davis, T. R., Pierce, M. R., Novak, S. X., & Hougland, J. L. (2021). Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling. Open biology, 11(7), 210080. https://doi.org/10.1098/rsob.210080
Abizaid, A., & Hougland, J. L. (2020). Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity. Trends in endocrinology and metabolism: TEM, 31(2), 107–117. https://doi.org/10.1016/j.tem.2019.09.006

Read the full article at: https://www.nature.com/articles/s41598-019-38549-z#citeas