Involvement of the ghrelin system in the maintenance of oxycodone self-administration: converging evidence from endocrine, pharmacologic and transgenic approaches

Hot Off the Press – February 7, 2022

Published in Molecular Psychiatry by Zhi-Bing You and Lorenzo Leggio et, al. at NIDA IRP.

Ghrelin, an orexigenic hormone, has recently emerged as a critical biological substrate implicated in drug reward. However, the reciprocal interactions between the endogenous ghrelin system and drug-motivated behaviors remain to be understood. With a variety of experimental approaches in this study, we find that acquisition of oxycodone-taking behaviors in rat is associated with elevations in the function of the endogenous ghrelin system as demonstrated by increased circulating ghrelin levels as a result of oxycodone-taking plus upregulated ghrelin receptor mRNA levels in dopamine neurons in the ventral tegmental area (VTA), a neuronal population critical for reward-taking. Pharmacological blockade of the ghrelin receptor decreases oxycodone-taking and incentive motivation for oxycodone-taking in rats and inhibits brain stimulation reward maintained by optogenetic stimulation of VTA dopamine neurons in mice. Our findings suggest that elevation of ghrelin signaling by oxycodone-motivated behavior is a causal process by which oxycodone motivates drug-taking, and that targeting the ghrelin system may be a viable treatment approach for opioid use disorders.

Publication Information

You, Zhi-Bing; Gardner, Eliot L; Galaj, Ewa; Moore, Allamar R; Buck, Tristram; Jordan, Chloe J; Humburg, Bree A; Bi, Guo-Hua; Xi, Zheng-Xiong; Leggio, Lorenzo

Involvement of the ghrelin system in the maintenance of oxycodone self-administration: converging evidence from endocrine, pharmacologic and transgenic approaches Journal Article

In: Mol Psychiatry, 2022, ISSN: 1476-5578.

Abstract | Links

@article{pmid35064236,

title = {Involvement of the ghrelin system in the maintenance of oxycodone self-administration: converging evidence from endocrine, pharmacologic and transgenic approaches},

author = {Zhi-Bing You and Eliot L Gardner and Ewa Galaj and Allamar R Moore and Tristram Buck and Chloe J Jordan and Bree A Humburg and Guo-Hua Bi and Zheng-Xiong Xi and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/35064236/},

doi = {10.1038/s41380-022-01438-5},

issn = {1476-5578},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Mol Psychiatry},

abstract = {Ghrelin, an orexigenic hormone, has emerged as a critical biological substrate implicated in drug reward. However, the response of the ghrelin system to opioid-motivated behaviors and the role of ghrelin in oxycodone self-administration remain to be studied. Here, we investigated the reciprocal interactions between the endogenous ghrelin system and oxycodone self-administration behaviors in rats and the role of the ghrelin system in brain stimulation reward (BSR) driven by optogenetic stimulation of midbrain reward circuits in mice. Oxycodone self-administration significantly elevated plasma ghrelin, des-acyl ghrelin and growth hormone and showed no effect on plasma LEAP2, a newly identified endogenous ghrelin receptor (GHS-R1a) antagonist. Oxycodone self-administration produced significant decreases in plasma gastric inhibitory polypeptide and insulin. Acquisition of oxycodone self-administration significantly upregulated GHS-R1a mRNA levels in dopamine neurons in the ventral tegmental area (VTA), a brain region critical in drug reward. Pretreatment with JMV2959, a selective GHS-R1a antagonist, dose-dependently reduced oxycodone self-administration and decreased the breakpoint for oxycodone under a progressive ratio reinforcement in Long-Evans rats. The inhibitory effects of JMV2959 on oxycodone self-administration is selectively mediated by GHS-R1a as JMV2959 showed a similar effect in Wistar wildtype but not in GHS-R knockout rats. JMV2959 pretreatment significantly inhibited BSR driven by selective stimulation of VTA dopamine neurons, but not by stimulation of striatal GABA neurons projecting to the VTA in mice. These findings suggest that elevation of ghrelin signaling by oxycodone or oxycodone-associated stimuli is a causal process by which oxycodone motivates oxycodone drug-taking and targeting the ghrelin system may be a viable treatment approach for opioid use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}