Biochemical and biophysical research communications · 2026
Role of the orphan nuclear receptor NR4A1 in mediating alcohol withdrawal-associated anxiety-like behaviors.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Yanjie, Wu Fei, Xu Zhigang, Li Xiangxue, Zhao Kangqing, Ni Zhaojun, Cheng Guiding, Zhang Zhong, Wang Dan, Wang Chuansheng, Wang Huiying, Gao Xuejiao, Zhang Ruiling, Sun Hongqiang
Аннотация
BACKGROUND: Anxiety induced by alcohol withdrawal is a crucial target for treating alcohol dependence (AD). Anxiety has been linked to prefrontal cortex neuron apoptosis. Studies have also indicated that nuclear receptor subfamily 4 group A member 1 (NR4A1) is associated with both anxiety and apoptosis. However, it remains uncertain whether NR4A1 is involved in anxiety-like behaviors induced by alcohol withdrawal through the regulation of the apoptosis of prefrontal cortex (PFC) neurons.
METHODS: We established an alcohol preference mouse model using the CPP paradigm, followed by 16 h of alcohol (20% ethanol; 2 g/kg/day, i.p.) abstinence. We also generated NR4A1 conditional knockout mice using the Cre-LoxP system. The anxiety-like behaviors caused by alcohol withdrawal were detected by the open field test, light/dark box test and elevated plus maze test in three groups: the control group, ethanol group, and NR4A1 knockout plus alcohol-treated group. Western blotting, real-time PCR and immunofluorescence were employed to assess the expression of NR4A1, B-cell lymphoma 2 (BCL2), BCL2 associated X protein (BAX), and caspase3 in the three groups. Immunofluorescence and co-immunoprecipitation were used to investigate the co-localization and binding of NR4A1 and BCL2, respectively.
RESULTS: Our findings clearly demonstrated that alcohol promoted the expression of pro-apoptosis-related genes, e.g., BAX and caspase3. We also found that alcohol not only promotes the expression of NR4A1 and BCL2 but also enhances their interaction. This interaction subsequently leads to the transformation of BCL2, shifting its role from that of an anti-apoptotic factor to that of a pro-apoptotic factor. The upregulation of pro-apoptotic proteins and anti-apoptotic proteins leads to neuronal apoptosis and contributes to anxiety-like behavior during alcohol withdrawal. NR4A1 conditional knockout is largely correlated with a reduction in the apoptosis of prefrontal neurons and alleviates anxiety-like behavior caused by alcohol withdrawal.
CONCLUSIONS: These findings indicate that NR4A1 is involved in the anxiety-like behavior induced by alcohol withdrawal through reversing the anti-apoptotic function of BCL2 and promoting the expression of BAX and caspase3.
METHODS: We established an alcohol preference mouse model using the CPP paradigm, followed by 16 h of alcohol (20% ethanol; 2 g/kg/day, i.p.) abstinence. We also generated NR4A1 conditional knockout mice using the Cre-LoxP system. The anxiety-like behaviors caused by alcohol withdrawal were detected by the open field test, light/dark box test and elevated plus maze test in three groups: the control group, ethanol group, and NR4A1 knockout plus alcohol-treated group. Western blotting, real-time PCR and immunofluorescence were employed to assess the expression of NR4A1, B-cell lymphoma 2 (BCL2), BCL2 associated X protein (BAX), and caspase3 in the three groups. Immunofluorescence and co-immunoprecipitation were used to investigate the co-localization and binding of NR4A1 and BCL2, respectively.
RESULTS: Our findings clearly demonstrated that alcohol promoted the expression of pro-apoptosis-related genes, e.g., BAX and caspase3. We also found that alcohol not only promotes the expression of NR4A1 and BCL2 but also enhances their interaction. This interaction subsequently leads to the transformation of BCL2, shifting its role from that of an anti-apoptotic factor to that of a pro-apoptotic factor. The upregulation of pro-apoptotic proteins and anti-apoptotic proteins leads to neuronal apoptosis and contributes to anxiety-like behavior during alcohol withdrawal. NR4A1 conditional knockout is largely correlated with a reduction in the apoptosis of prefrontal neurons and alleviates anxiety-like behavior caused by alcohol withdrawal.
CONCLUSIONS: These findings indicate that NR4A1 is involved in the anxiety-like behavior induced by alcohol withdrawal through reversing the anti-apoptotic function of BCL2 and promoting the expression of BAX and caspase3.