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Ghrelin Receptor Antagonism as a Potential Therapeutic Target for Alcohol Use Disorders: A Preclinical Perspective

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Book cover Central Functions of the Ghrelin Receptor

Part of the book series: The Receptors ((REC,volume 25))

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Abstract

The rewarding properties of natural and chemical reinforcers are mediated via the reward systems, such as the cholinergic-dopaminergic reward link. A dysfunction in these reward systems underlies development of addictive behaviours such as alcohol use disorder. By elucidating the complex neurobiological mechanisms involved in the drug-induced activation of the mesolimbic dopamine system, novel treatment strategies can be identified. Recent work has suggested that the gut–brain peptide ghrelin may be such candidates. Indeed, the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link. Ghrelin may thereby increase the incentive salience for motivated behaviours such as reward seeking. Moreover, preclinical findings show that ghrelin signalling is required for reward induced by alcohol, for the motivation to consume alcohol and for the intake of alcohol in rodents. Reward induced by other additive drugs such as nicotine, cocaine and amphetamine also involve ghrelin and its receptor. Human genetic data support a role for ghrelin in drug reward. Polymorphisms in ghrelin-related genes are associated with increased alcohol intake, smoking as well as amphetamine dependence in humans. Furthermore, plasma levels of ghrelin are associated with alcohol dependence as well as with craving. Finally, another gut–brain peptide known to regulate food intake, i.e., the anorectic peptide glucagone-like-peptide-1 (GLP-1), was recently shown to regulate drug reinforcement. Peripheral treatment with a GLP-1 analogue attenuated alcohol-induced reward as well as decreased alcohol intake and alcohol seeking behaviour in rodents. In addition, GLP-1 analogues appear to attenuate drug-induced reward. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of addictive behaviours such as alcohol dependence.

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Acknowledgment

The book chapter was supported by grants from the Swedish Research Council (grant no. K2006-21X-04247-33-3, 2009-2782 and K2010-80X-21496-01-6), The Swedish brain foundation, LUA/ALF (grant no. 148251) from the Sahlgrenska University Hospital, Alcohol research council of the Swedish alcohol retailing monopoly and the foundations of Adlerbertska, Fredrik and Ingrid Thuring, Tore Nilsson, Längmanska, Torsten and Ragnar Söderberg, Wilhelm and Martina Lundgren, NovoNordisk, Knut and Alice Wallenberg, Magnus Bergvall, Anérs, Jeansons, Åke Wiberg, the Swedish Society of Medicine, Swedish Society for Medical Research.

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  1. Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, PO Box 431, SE-405 30, Gothenburg, Sweden

    Elisabet Jerlhag & Jörgen A. Engel

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  1. Elisabet Jerlhag
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Correspondence to Elisabet Jerlhag .

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  1. Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium

    Jeanelle Portelli

  2. Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium

    Ilse Smolders

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Jerlhag, E., Engel, J.A. (2014). Ghrelin Receptor Antagonism as a Potential Therapeutic Target for Alcohol Use Disorders: A Preclinical Perspective. In: Portelli, J., Smolders, I. (eds) Central Functions of the Ghrelin Receptor. The Receptors, vol 25. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0823-3_7

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