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

Molecular Psychiatry volume 27, pages 2171–2181 (2022)Cite this article

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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.

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Fig. 1: Plasma ghrelin, DAG, LEAP2, growth hormone, GIP and insulin levels as a function of oxycodone self-administration.
Fig. 2: Effects of acquisition of oxycodone self-administration on GHS-R1a mRNA expression in the VTA.
Fig. 3: Effects of GHS-R1a blockade by JMV2959 on oxycodone self-administration (50 μg/kg/infusion) in Long-Evans and Wistar GHS-R KO and WT rats.
Fig. 4: Effects of GHS-R1a blockade by JMV2959 on oxycodone self-administration tested under a low oxycodone unit dose (12.5 µg/kg/infusion) and under a PR schedule of reinforcement.
Fig. 5: Impact of GHS-R1a blockade by JMV2959 on BSR maintained by optogenetic self-stimulation of VTA dopamine neurons in DAT-Cre mice and NAS GABA neurons to VTA in vGAT-Cre mice.

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Acknowledgements

This work was supported by the Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA; to all authors) and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism (to LL). We thank the Medication Development Program (MDP), the IRP, NIDA for support and Dr. Gail Seabold (NIDA) for edits and proofreading the manuscript.

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  1. Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA

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

  2. Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, Baltimore, MD, USA

    Lorenzo Leggio

  3. Medication Development Program, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA

    Lorenzo Leggio

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LL, ZBY and ELG designed the experiments. ZBY, EG, ARM, TB, CJJ, BAH and GHB conducted the experiments. ZBY, EG and CJJ performed the data analysis. ZBY, LL, ELG EG and ZXX wrote the manuscript.

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Correspondence to Lorenzo Leggio.

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You, ZB., Gardner, E.L., Galaj, E. et al. Involvement of the ghrelin system in the maintenance of oxycodone self-administration: converging evidence from endocrine, pharmacologic and transgenic approaches. Mol Psychiatry 27, 2171–2181 (2022). https://doi.org/10.1038/s41380-022-01438-5

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