N-oleoyl glycine and N-oleoyl alanine attenuate alcohol self-administration and preference in mice

Samah Shahen-Zoabi, Reem Smoum, Alexey Bingor, Etty Grad, Alina Nemirovski, Tawfeeq Shekh-Ahmad, Raphael Mechoulam, Rami Yaka

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and has an important role in the neurobiological processes underlying drug addiction. We have previously shown that an elevated ECS response to psychostimulant (cocaine) is involved in regulating the development and expression of cocaine-conditioned reward and sensitization. We therefore hypothesized that drug-induced elevation in endocannabinoids (eCBs) and/or eCB-like molecules (eCB-Ls) may represent a protective mechanism against drug insult, and boosting their levels exogenously may strengthen their neuroprotective effects. Here, we determine the involvement of ECS in alcohol addiction. We first measured the eCBs and eCB-Ls levels in different brain reward system regions following chronic alcohol self-administration using LC–MS. We have found that following chronic intermittent alcohol consumption, N-oleoyl glycine (OlGly) levels were significantly elevated in the prefrontal cortex (PFC), and N-oleoyl alanine (OlAla) was significantly elevated in the PFC, nucleus accumbens (NAc) and ventral tegmental area (VTA) in a region-specific manner. We next tested whether exogenous administration of OlGly or OlAla would attenuate alcohol consumption and preference. We found that systemic administration of OlGly or OlAla (60 mg/kg, intraperitoneal) during intermittent alcohol consumption significantly reduced alcohol intake and preference without affecting the hedonic state. These findings suggest that the ECS negatively regulates alcohol consumption and boosting selective eCBs exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse.

Original languageEnglish
Article number273
JournalTranslational Psychiatry
Issue number1
StatePublished - 31 Jul 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).


This work was funded by PlantEXT Ltd, the Israel Science Foundation (ISF; 1283/16 RY), the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem (RY), and by IMRIC Hub for Addiction Research (ICARE, RY)

FundersFunder number
IMRIC Hub for Addiction Research
PlantEXT Ltd
Hebrew University of Jerusalem
Israel Science Foundation1283/16 RY


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