Details

Autor(en) / Beteiligte

• Godlewski, Grzegorz
• Cinar, Resat
• Coffey, Nathan J.
• Liu, Jie
• Jourdan, Tony
• Mukhopadhyay, Bani
• Chedester, Lee
• Liu, Ziyi
• Osei-Hyiaman, Douglas
• Iyer, Malliga R.
• Park, Joshua K.
• Smith, Roy G.
• Iwakura, Hiroshi
• Kunos, George

Titel

Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis

Ist Teil von

• Cell metabolism, 2019-06, Vol.29 (6), p.1320-1333.e8

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •CB1R and ghrelin work together to promote alcohol intake via a gut-brain axis•Alcohol intake is inhibited by CB1R blockade, but only when ghrelin signaling is intact•Inhibition of peripheral CB1R reduces plasma levels of biologically active ghrelin•CB1R blockade promotes the degradation of the substrate needed to activate ghrelin Endocannabinoids and ghrelin are both implicated in promoting alcohol intake. Godlewski et al. show that cannabinoid-1 receptor (CB1R) signaling in ghrelin-producing stomach cells modulates the formation of biologically active octanoyl-ghrelin which then acts via gastric vagal afferents to promote alcohol consumption. They further show that peripherally-restricted pharmacological inhibition of CB1R reduces ethanol drinking in mice.