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

Abstract

Highlights d CB 1 R and ghrelin work together to promote alcohol intake via a gut-brain axis d Alcohol intake is inhibited by CB 1 R blockade, but only when ghrelin signaling is intact d Inhibition of peripheral CB 1 R reduces plasma levels of biologically active ghrelin d CB 1 R blockade promotes the degradation of the substrate needed to activate ghrelin

A Guide to Targeting the Endocannabinoid System in Drug Design

“…It suggests the important impact of peripheral CB1 in healthy mammals on addictions. Therefore, CB1 peripheral antagonism emerges as a valid strategy with the reduced risk of central adverse effects [133].…”

Interactions Between Alcohol and the Endocannabinoid System

“…A recent study explored whether a similar periphery‐to‐brain axis may be involved in regulating alcohol‐seeking behavior, using the peripheral CB 1 R inverse agonist JD5037 in a 2‐bottle/free choice as well as a limited access, drinking in the dark paradigm, and male mice on a C57Bl6/J background (Godlewski et al, 2019). JD5037 treatment significantly reduced EtOH preference and intake in wild‐type mice but not in mice deficient in CB 1 R, ghrelin, or the ghrelin receptor GHSR 1A , indicating that the stomach‐derived hormone ghrelin may be the link between peripheral CB 1 R and the CNS structures controlling alcohol drinking behavior.…”

“…This was supported by the reduced alcohol preference, which was unaffected by JD5037 treatment in mice deficient in Mboat4 , the gene encoding GOAT. Ghrelin‐producing MGN3‐1 mouse stomach ghrelinoma cells express CB 1 R and generate high levels of endocannabinoids (Godlewski et al, 2019), similar to primary ghrelin‐producing cells of the stomach mucosa (Engelstoft et al, 2013). In MGN3‐1 cells incubated with deuterated palmitic acid, JD5037 reduced the level of the substrate octanoyl‐carnitine generated from palmitoyl‐carnitine by increasing the rate of fatty acid β ‐oxidation, which reduced the amount of octanoyl‐ghrelin generated by these cells.…”

“…Finally, blocking vagal afferents, which express GHSR 1A , abrogated the ability of either CB 1 R or GHSR 1A blockade to reduce alcohol drinking. This suggests that octanoyl‐ghrelin released by ghrelin‐producing cells activates GHSR 1A on neighboring vagal afferent terminals to generate a neural signal to brain structures involved in the control of alcohol drinking behavior (Godlewski et al, 2019). This mechanism is schematically illustrated in Fig.…”

“…In contrast to the selective modulation of octanoyl‐ghrelin levels by CB 1 R, norepinephrine released from sympathetic nerves and activating β 2 ‐adrenergic receptors ( β 2 R) stimulates the release of both desacyl‐ and octanoyl‐ghrelin, which also promotes alcohol drinking that can be antagonized by the β R‐blocker propranolol. Reproduced from Godlewski and colleagues (2019).…”