Targeting Peripheral CB 1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis

Cell Metab. 2019 Jun 4;29(6):1320-1333.e8. doi: 10.1016/j.cmet.2019.04.012. | PubMed

Grzegorz Godlewski¹, Resat Cinar², Nathan J Coffey², Jie Liu², Tony Jourdan², Bani Mukhopadhyay², Lee Chedester², Ziyi Liu², Douglas Osei-Hyiaman², Malliga R Iyer², Joshua K Park², Roy G Smith³, Hiroshi Iwakura⁴, George Kunos⁵

1. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: greg.godlewski@nih.gov.
2. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
3. Scripps Research Institute, Jupiter, FL 33458, USA.
4. Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
5. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: george.kunos@nih.gov.

Abstract

Endocannabinoids acting on the cannabinoid-1 receptor (CB1R) or ghrelin acting on its receptor (GHS-R1A) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CB1R inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CB1R, ghrelin peptide or GHS-R1A. JD5037 treatment of alcohol-drinking mice inhibits 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 by increasing 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 blocking CB1R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB1R blockade may have therapeutic potential in the treatment of alcoholism.

Presented By Grzegorz Godlewski