Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA; Alcohol & Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA; Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Alcohol. 2019 Mar;75:11-18. doi: 10.1016/j.alcohol.2018.04.006. Epub 2018 Apr 19.
Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disease characterized by the emergence of negative emotional states and the development of motivational deficits that manifest during alcohol withdrawal. Accordingly, alcohol may be sought after and taken in excessive amounts to alleviate withdrawal-related symptoms. To develop more effective treatments for AUD, it is necessary to identify potential molecular targets that underlie the transition from initial alcohol use to alcohol dependence, and our previous work has implicated a role for potentiated glucocorticoid receptor (GR) signaling in this regard. As a key negative regulator of GR-mediated signaling, the current study first measured c-Jun N-terminal kinase (JNK) phosphorylation in animals following an acute alcohol challenge. We found that JNK phosphorylation (pJNK) was significantly increased in the hippocampus, frontal cortical regions, and striatum of adult male Wistar rats following alcohol challenge, indicating that initial alcohol exposure increases JNK activity across several brain regions. A separate group of adult male Wistar rats were made dependent via chronic, intermittent ethanol vapor exposure and were trained to self-administer alcohol. We found that alcohol-dependent animals consumed significantly more alcohol and escalated their drinking over time compared to non-dependent animals. We then measured alterations in JNK phosphorylation in this alcohol-dependent group during acute withdrawal and found that pJNK was selectively decreased in the dorsal hippocampus, dorsomedial prefrontal cortex, and cingulate cortex. These findings demonstrate that withdrawal from chronic alcohol exposure leads to region-specific deficits in JNK phosphorylation. JNK signaling dysregulation may foster long-lasting behavioral and motivational impairments in alcohol dependence, either as a result of increased GR-mediated stress signaling or via other downstream mechanisms.
酒精使用障碍（AUD）是一种慢性、复发性精神疾病，其特征为负性情绪状态的出现和动机缺陷的发展，这些在酒精戒断期间表现出来。因此，人们可能会寻求并过量饮酒以缓解与戒断相关的症状。为了开发更有效的 AUD 治疗方法，有必要确定潜在的分子靶点，这些靶点是从最初的酒精使用到酒精依赖的转变的基础。我们之前的工作表明，增强的糖皮质激素受体（GR）信号在这方面起作用。作为 GR 介导的信号的关键负调节剂，本研究首先在急性酒精挑战后测量了动物中的 c-Jun N 末端激酶（JNK）磷酸化。我们发现，在酒精挑战后，成年雄性 Wistar 大鼠的海马体、额皮质区域和纹状体中的 JNK 磷酸化（pJNK）显著增加，这表明最初的酒精暴露会增加多个脑区域的 JNK 活性。另一组成年雄性 Wistar 大鼠通过慢性间歇性乙醇蒸气暴露而变得依赖，并接受酒精自我给药训练。我们发现，与非依赖动物相比，酒精依赖动物在急性戒断期间消耗的酒精明显更多，并且随着时间的推移逐渐增加。然后，我们在这个酒精依赖组中测量了 JNK 磷酸化的变化，发现 pJNK 选择性地减少了背侧海马体、背侧前额皮质和扣带皮质。这些发现表明，慢性酒精暴露戒断会导致 JNK 磷酸化的特定区域缺陷。JNK 信号转导失调可能会在酒精依赖中导致持久的行为和动机损伤，要么是由于 GR 介导的应激信号增加，要么是通过其他下游机制。
