Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Biochemistry

Introduction: 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. Objectives: In this study, we assessed the possibility of using agomelatine for the treatment of these symptoms in the rat model of alcoholism and the possible role of Notch1 signaling. 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 (50mg/kg/day) orally from day 61 to 82, followed by behavioral, histopathological, and biochemical assessment. Results: Agomelatine treatment caused a 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, Per2, and 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

Issued also as CD