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Endocannabinoids Promote Ethanol Drinking Via Cb 1 Receptor-Mediated Increase in Ghrelin Acylation and Signaling in the Stomach

48 Pages Posted: 26 Feb 2019 Sneak Peek Status: Published

See all articles by Grzegorz Godlewski

Grzegorz Godlewski

National Institutes of Health - Laboratory of Physiologic Studies

Resat Cinar

National Institutes of Health - Laboratory of Physiologic Studies

Nathan Coffey

National Institutes of Health - Laboratory of Physiologic Studies

Jie Liu

National Institutes of Health - Laboratory of Physiologic Studies

Tony Jourdan

National Institutes of Health - Laboratory of Physiologic Studies

Bani Mukhopadhyay

National Institutes of Health - Laboratory of Physiologic Studies

Lee Chedester

National Institutes of Health - Laboratory of Physiologic Studies

Ziyi Liu

National Institutes of Health - Laboratory of Physiologic Studies

Douglas Osei-Hyiaman

National Institutes of Health - Laboratory of Physiologic Studies

Malliga R. Iyer

National Institutes of Health - Laboratory of Physiologic Studies

Joshua Park

National Institutes of Health - Laboratory of Physiologic Studies

Roy G. Smith

The Scripps Research Institute

Hiroshi Iwakura

Wakayama Medical University

George Kunos

National Institutes of Health - Laboratory of Physiologic Studies

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Abstract

The dynamic interplay between energy homeostasis and motivational behavior is exemplified by mediators involved in regulating both. Endocannabinoids acting via CB1 receptors (CB1R) or the stomach-derived hormone ghrelin acting via ghrelin receptors (GHS-R1A) both promote food intake and support alcohol seeking behavior. Here we report that the peripheral CB1R antagonist JD5037 reduces ethanol drinking in mice by inhibiting the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin. In ghrelin-producing stomach cells, JD5037 reduced the level of the substrate octanoyl-carnitine generated from palmitoyl-carnitine due to increased fatty acid β-oxidation. Blocking gastric vagal afferents abrogated the ability of either CB1R or GHS-R1A blockade to reduce ethanol drinking. We conclude that blockade of CB1R in ghrelin-producing cells inhibits the formation of biologically active ghrelin and its signaling via gastric vagal afferents to facilitate voluntary ethanol intake. Thus, peripheral CB1R blockade affecting the gut-brain axis may have therapeutic potential in alcoholism.

Suggested Citation

Godlewski, Grzegorz and Cinar, Resat and Coffey, Nathan and Liu, Jie and Jourdan, Tony and Mukhopadhyay, Bani and Chedester, Lee and Liu, Ziyi and Osei-Hyiaman, Douglas and Iyer, Malliga R. and Park, Joshua and Smith, Roy G. and Iwakura, Hiroshi and Kunos, George, Endocannabinoids Promote Ethanol Drinking Via Cb 1 Receptor-Mediated Increase in Ghrelin Acylation and Signaling in the Stomach (January 16, 2019). Available at SSRN: https://ssrn.com/abstract=3316795 or http://dx.doi.org/10.2139/ssrn.3316795
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Grzegorz Godlewski

National Institutes of Health - Laboratory of Physiologic Studies ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Resat Cinar

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Nathan Coffey

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Jie Liu

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Tony Jourdan

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Bani Mukhopadhyay

National Institutes of Health - Laboratory of Physiologic Studies ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Lee Chedester

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Ziyi Liu

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Douglas Osei-Hyiaman

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Malliga R. Iyer

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Joshua Park

National Institutes of Health - Laboratory of Physiologic Studies

9000 Rockville Pike
Bethesda, MD 20892
United States

Roy G. Smith

The Scripps Research Institute

United States

Hiroshi Iwakura

Wakayama Medical University

Wakayama
Japan

George Kunos (Contact Author)

National Institutes of Health - Laboratory of Physiologic Studies ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

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