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Ghrelin receptor antagonism of morphine-induced accumbens dopamine release and behavioral stimulation in rats

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Abstract

Rationale and objectives

Ghrelin, an orexigenic (appetite stimulating) peptide activates binding sites in the ventral tegmental area (a structure linked with the neural reward system) allowing it to participate in reward-seeking behavior. An increasing number of studies over the past few years have demonstrated ghrelin’s role in alcohol, cocaine, and nicotine abuse. However, the role of ghrelin, in opioid effects, has rarely been examined. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit markers of morphine-induced activation of the neural reward system, namely morphine-induced increase of dopamine in the nucleus accumbens and behavioral changes in rats.

Methods

We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens shell in rats following morphine (MO, 5, 10 mg/kg s.c.) administration with and without ghrelin antagonist pretreatment (JMV2959, 3, 6 mg/kg i.p., 20 min before MO). Induced behavioral changes were simultaneously monitored.

Results

JMV2959 significantly and dose dependently reduced MO-induced dopamine release in the nucleus accumbens shell and affected concentration of by-products associated with dopamine metabolism: 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). JMV2959 pretreatment also significantly reduced MO-induced behavioral stimulation, especially stereotyped behavior.

Conclusions

Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.

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Acknowledgments

We thank Ms. Marketa Dvorakova, Mrs. Blanka Mairychova and Mrs. Eva Sulcova from the Department of Pharmacology, and Ass. Prof. Petr Zach, MD. PhD from the Department of Anatomy, Third Faculty of Medicine, Charles University, Prague for their excellent technical assistance. The GHS-R1A antagonist JMV2959 was kindly provided by Anton Bespalov, AbbVie, Germany under a material transfer agreement. This study was supported by the Grant Agency of the Ministry of Health of the Czech Republic—IGA NT/13687-3/2012, by the Grant Agency of the Charles University—GAUK 54313, by Charles University in Prague, Project PRVOUK P34 and Project 266705/SVV/2013.

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Authors and Affiliations

  1. Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, Prague 10, 100 34, Czech Republic

    Magdalena Sustkova-Fiserova, Pavel Jerabek, Tereza Havlickova & Miloslav Krsiak

  2. Laboratory of Medicinal Diagnostics, Department of Organic Technology ICT, Technicka 5, Prague 6, 166 28, Czech Republic

    Petr Kacer

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  1. Magdalena Sustkova-Fiserova
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  2. Pavel Jerabek
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  5. Miloslav Krsiak
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Correspondence to Magdalena Sustkova-Fiserova.

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Sustkova-Fiserova, M., Jerabek, P., Havlickova, T. et al. Ghrelin receptor antagonism of morphine-induced accumbens dopamine release and behavioral stimulation in rats. Psychopharmacology 231, 2899–2908 (2014). https://doi.org/10.1007/s00213-014-3466-9

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  • DOI: https://doi.org/10.1007/s00213-014-3466-9

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