Xiaomeng Qiao1, Haiyun Gai2, Rui Su1, Cuola Deji1, Jingjing Cui1, Jianghua Lai3, Yongsheng Zhu4. 1. College of Forensic Science, School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi 710061, China. 2. Xi'an Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi 710021, China. 3. College of Forensic Science, School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China. 4. College of Forensic Science, School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi 710061, China. Electronic address: aiwapeter@163.com.
Abstract
BACKGROUND: Alcohol abuse and anxiety disorders often occur concurrently, but their underlying cellular mechanisms remain unclear. Neuroadaptation within the medial prefrontal cortex (mPFC) have been implicated in the molecular mechanisms underlying alcohol drinking behavior and withdrawal. METHODS: A chronic alcohol exposure rat model (35 consecutive days of 10% alcohol intake and 48 h of withdrawal) was established, then, wortmannin (0.5 µg/side) was injected bilaterally into the mPFC. The elevated plus maze (EPM) and open field test (OFT) were used to assess anxiety-like behavior. Western blot assays were used to assess protein levels. RESULTS: We found that anxiety-like behavior peaked approximately 6 h after alcohol withdrawal. However, wortmannin greatly decreased alcohol intake and attenuated anxiety-like behavior in the alcohol exposure rats. Moreover, the PI3K-AKT-GSK3β signaling pathway was activated after alcohol withdrawal, and phosphorylation of the downstream cAMP response element-binding protein (CREB) was increased. Wortmannin uniformly reversed PI3K-AKT-GSK3β-CREB pathway phosphorylation. LIMITATIONS: The downstream GSK3β activity was not intervened and a single dose level of wortmannin was used. CONCLUSION: Our results suggest that activating the PI3K-AKT-GSK3β-CREB pathway in the mPFC is an important contributor to the molecular mechanisms underlying alcohol withdrawal. PI3K signaling pathway inhibitors are thus potential candidates for treating alcohol abuse.
BACKGROUND:Alcohol abuse and anxiety disorders often occur concurrently, but their underlying cellular mechanisms remain unclear. Neuroadaptation within the medial prefrontal cortex (mPFC) have been implicated in the molecular mechanisms underlying alcohol drinking behavior and withdrawal. METHODS: A chronic alcohol exposure rat model (35 consecutive days of 10% alcohol intake and 48 h of withdrawal) was established, then, wortmannin (0.5 µg/side) was injected bilaterally into the mPFC. The elevated plus maze (EPM) and open field test (OFT) were used to assess anxiety-like behavior. Western blot assays were used to assess protein levels. RESULTS: We found that anxiety-like behavior peaked approximately 6 h after alcohol withdrawal. However, wortmannin greatly decreased alcohol intake and attenuated anxiety-like behavior in the alcohol exposure rats. Moreover, the PI3K-AKT-GSK3β signaling pathway was activated after alcohol withdrawal, and phosphorylation of the downstream cAMP response element-binding protein (CREB) was increased. Wortmannin uniformly reversed PI3K-AKT-GSK3β-CREB pathway phosphorylation. LIMITATIONS: The downstream GSK3β activity was not intervened and a single dose level of wortmannin was used. CONCLUSION: Our results suggest that activating the PI3K-AKT-GSK3β-CREB pathway in the mPFC is an important contributor to the molecular mechanisms underlying alcohol withdrawal. PI3K signaling pathway inhibitors are thus potential candidates for treating alcohol abuse.
Authors: Megan K Mulligan; Lu Lu; Sonia A Cavigelli; Pierre Mormède; Elena Terenina; Wenyuan Zhao; Robert W Williams; Byron C Jones Journal: Alcohol Clin Exp Res Date: 2019-05-21 Impact factor: 3.455
Authors: Reesha R Patel; Sarah A Wolfe; Vittoria Borgonetti; Pauravi J Gandhi; Larry Rodriguez; Angela E Snyder; Shannon D'Ambrosio; Michal Bajo; Alain Domissy; Steven Head; Candice Contet; R Dayne Mayfield; Amanda J Roberts; Marisa Roberto Journal: Mol Psychiatry Date: 2022-06-06 Impact factor: 13.437
Authors: Shahnawaz A Bhat; Rebecca J Henry; Alexa C Blanchard; Bogdan A Stoica; David J Loane; Alan I Faden Journal: J Neurochem Date: 2020-01-28 Impact factor: 5.546