PI3K-AKT-GSK3β-CREB signaling pathway regulates anxiety-like behavior in rats following alcohol withdrawal

Abstract

BackgroundAlcohol 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. MethodsA 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. ResultsWe 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. LimitationsThe downstream GSK3β activity was not intervened and a single dose level of wortmannin was used. ConclusionOur 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.