Aim

Alcohol abuse is a significant causative factor of death worldwide. The Notch1 signaling pathway is involved in alcohol tolerance, withdrawal and dependence. Agomelatine is a known antidepressant acting as a melatonin receptor (MT1/2) agonist and a 5-hydroxytryptamine receptor-2C antagonist. However, its effects on alcohol cravings and alcohol withdrawal symptoms have not been investigated. In this study, we assessed the possibility of using agomelatine for the treatment of these symptoms in a rat model of alcoholism and the possible role of Notch1 signaling.

Main methods

We induced alcoholism in rats using a free-choice drinking model for 60 days. From day 61, free-choice was continued until day 82 for the craving model, whereas only water was offered in the withdrawal model. Meanwhile, the treated groups for both models received agomelatine (50 mg/kg/day) orally from day 61 to 82, followed by behavioral, histopathological and biochemical assessment.

Key findings

Agomelatine treatment caused significant decrease in alcohol consumption with a positive effect on anxiety-like behavior in the open field, memory in the Morris water maze and immobility in the forced swim test. Moreover, agomelatine induced the expression of Notch1 pathway markers, including Notch1, NICD, CREB, CCNE-2, Hes-1, both total and phosphorylated ERK1/2, MMP9, Per2and RGS-2 in the hippocampal formation. By contrast, NMDAR expression was reduced. Furthermore, agomelatine normalized the serum levels of BDNF, cortisol, dopamine and glutamate which were disrupted by alcohol consumption.

Significance

Based on these findings, agomelatine reversed alcohol cravings and withdrawal symptoms associated with alcohol dependence by modulating the Notch1 signaling pathway.

中文翻译：

---

阿戈美拉汀通过调节大鼠 Notch1 信号通路减轻酒精渴望和戒断症状

目的

酗酒是世界范围内导致死亡的一个重要因素。Notch1 信号通路涉及酒精耐受、戒断和依赖。阿戈美拉汀是一种已知的抗抑郁药，作为褪黑激素受体 (MT1/2) 激动剂和 5-羟色胺受体-2C 拮抗剂。然而，尚未研究其对酒精渴望和酒精戒断症状的影响。在这项研究中，我们评估了在酒精中毒大鼠模型中使用阿戈美拉汀治疗这些症状的可能性以及 Notch1 信号传导的可能作用。

主要方法

我们使用自由选择饮酒模型诱导大鼠酗酒 60 天。从第 61 天开始，渴望模型的自由选择一直持续到第 82 天，而在戒断模型中只提供水。同时，两种模型的治疗组从第 61 天到第 82 天口服阿戈美拉汀（50 mg/kg/天），然后进行行为、组织病理学和生化评估。

主要发现

阿戈美拉汀治疗导致饮酒量显着减少，对开放场地中的焦虑样行为、莫里斯水迷宫中的记忆和强迫游泳测试中的不动有积极影响。此外，阿戈美拉汀诱导海马形成中 Notch1 通路标志物的表达，包括 Notch1、NICD、CREB、CCNE-2、Hes-1、总和磷酸化 ERK1/2、MMP9、Per2 和 RGS-2。相比之下，NMDAR 表达减少。此外，阿戈美拉汀使因饮酒而受到干扰的 BDNF、皮质醇、多巴胺和谷氨酸的血清水平正常化。

意义

基于这些发现，阿戈美拉汀通过调节 Notch1 信号通路逆转了与酒精依赖相关的酒精渴望和戒断症状。