Fluoxetine improves behavioural deficits induced by chronic alcohol treatment by alleviating RNA editing of 5-HT2C receptors. (March 2020)

• Record Type: Journal Article
• Authors: Li, Zexiong; Lu, Yan; Liang, Shanshan; Li, Shuai; Chen, Beina; Zhang, Manman; Xia, Maosheng; Guan, Dawei; Verkhratsky, Alexei; Li, Baoman
• Is Part Of: Neurochemistry international. Volume 134(2020)
• Publication Date: 2020-03
• Subjects: 5-HT2C receptor -- Chronic alcohol addiction -- ADAR2 -- ATP -- Astrocytes; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2020.104689
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: The alcoholism and major depressive disorder are common comorbidity, with alcohol-induced depressive symptoms being eased by selective serotonin re-uptake inhibitors (SSRIs), although the mechanisms underlying pathology and therapy are poorly understood. Chronic alcohol consumption affects the activity of serotonin 2C receptors (5-HT2C R) by regulating adenosine deaminases acting on RNA (ADARs) in neurons. Astrogliopathic changes contribute to alcohol addiction, while decreased release of ATP from astrocytes can trigger depressive-like behaviours in mice. In this study, we discovered that chronic alcohol treatment increased editing of RNA of 5-HT2C R via up-regulating the expression of ADAR2, consequently reducing the release of ATP from astrocytes induced by 5-HT2C R agonist, MK212. Moreover, SSRI antidepressant fluoxetine decreased the expression of ADAR2 through the transactivation of EGFR/PI3K/AKT/cFos signalling pathway. The increased release of astroglial ATP by MK212 which was suppressed by chronic alcohol consumption, and reduction in ADAR2 activity eliminated the RNA editing of 5-HT2C R increased by alcohol in vitro and recovered the release of ATP from astrocytes induced by MK212. Meanwhile, fluoxetine improved the behavioural and motor symptoms induced by alcohol addiction and decreased the alcohol intake. Our study suggests that the astrocytic 5-HT2C R contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination. Graphical abstract: Image 1 Highlights: Alcohol increased RNA editing of 5-HT2C R via up-regulating ADAR2 in astrocytes. 5-HT2C R agonist MK212 stimulated ATP release from astrocytes. Fluoxetine down-regulated ADAR2 via transactivating EGFR in astrocytes. Fluoxetine suppressed RNA editing of 5-HT2C R induced by alcohol. Administration of fluoxetine decreased the alcohol preference in addiction model.