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.
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 version of the paper has not been formally peer reviewed.
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