TY - JOUR
T1 - Fluoxetine improves behavioural deficits induced by chronic alcohol treatment by alleviating RNA editing of 5-HT2C receptors
AU - Li, Zexiong
AU - Lu, Yan
AU - Liang, Shanshan
AU - Li, Shuai
AU - Chen, Beina
AU - Zhang, Manman
AU - Xia, Maosheng
AU - Guan, Dawei
AU - Verkhratsky, Alexei
AU - Li, Baoman
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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-HT2CR) 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-HT2CR via up-regulating the expression of ADAR2, consequently reducing the release of ATP from astrocytes induced by 5-HT2CR 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-HT2CR 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-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination.
AB - 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-HT2CR) 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-HT2CR via up-regulating the expression of ADAR2, consequently reducing the release of ATP from astrocytes induced by 5-HT2CR 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-HT2CR 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-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination.
U2 - 10.1016/j.neuint.2020.104689
DO - 10.1016/j.neuint.2020.104689
M3 - Article
SN - 0197-0186
VL - 134
SP - 104689
JO - Neurochemistry International
JF - Neurochemistry International
ER -
