Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
Transl Psychiatry. 2023 Jul 31;13(1):273. doi: 10.1038/s41398-023-02574-4.
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.
内源性大麻素系统（ECS）在大脑的突触可塑性和动态平衡过程中发挥着关键的调节作用，并且在药物成瘾的神经生物学过程中起着重要作用。我们之前的研究表明，内源性大麻素系统（ECS）对精神兴奋剂（可卡因）反应的升高，参与了可卡因条件性奖赏和敏化的发展和表达的调节。因此，我们假设药物诱导的内源性大麻素（eCBs）和/或内源性大麻素样分子（eCB-Ls）的升高可能代表了一种对抗药物损伤的保护机制，并且外源性地增加它们的水平可能会增强它们的神经保护作用。在这里，我们确定了 ECS 在酒精成瘾中的作用。我们首先使用 LC-MS 测量了慢性酒精自我给药后不同大脑奖励系统区域中的 eCBs 和 eCB-Ls 水平。我们发现，在慢性间歇性酒精消耗后，N-油酰甘氨酸（OlGly）水平在前额叶皮层（PFC）中显著升高，并且 N-油酰丙氨酸（OlAla）在 PFC、伏隔核（NAc）和腹侧被盖区（VTA）中以区域特异性的方式显著升高。接下来，我们测试了外源性给予 OlGly 或 OlAla 是否会减弱酒精的消耗和偏好。我们发现，在间歇性酒精消耗期间，系统给予 OlGly 或 OlAla（60mg/kg，腹腔内）显著减少了酒精的摄入和偏好，而不影响愉悦状态。这些发现表明，ECS 负调节酒精消耗，并且外源性地增强选择性 eCBs 具有对抗酒精消耗的有益作用，并且可能在预防复发方面具有作用。
