Somkuwar Sucharita S, Vendruscolo Leandro F, Fannon McKenzie J, Schmeichel Brooke E, Nguyen Tran Bao, Guevara Jasmin, Sidhu Harpreet, Contet Candice, Zorrilla Eric P, Mandyam Chitra D
VA San Diego Healthcare System, San Diego, CA, USA.
National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.
Psychoneuroendocrinology. 2017 Oct;84:17-31. doi: 10.1016/j.psyneuen.2017.06.006. Epub 2017 Jun 12.
Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre-abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naïve (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse.
酒精依赖与下丘脑 - 垂体 - 肾上腺轴功能失调有关。在此，我们研究了反复乙醇中毒 - 戒断周期（采用慢性间歇性乙醇蒸汽吸入法；CIE）以及停止CIE后的禁欲对血浆皮质酮（CORT）峰值和谷值水平的影响。在停止CIE后的不同时间段（2小时至28天）评估内侧前额叶皮质（mPFC）中的易怒和焦虑样行为以及糖皮质激素受体（GR）。结果显示，CORT峰值在CIE期间升高，在早期禁欲（1 - 11天）期间短暂下降，并在长期禁欲（17 - 27天）期间恢复到禁欲前水平。CIE急性戒断会增强攻击和焦虑样行为。CIE早期禁欲可减少焦虑样行为。在早期和长期禁欲期间的时间点测量时，mPFC - GR信号传导（以Ser211处GR的相对磷酸化作为指标）会短暂下降。此外，研究了CIE组（CIE - ED）和未接触CIE组（ED）大鼠在急性戒断（8小时）和长期禁欲（28天）期间的自愿乙醇饮用情况，以及CIE - ED和ED对CORT峰值水平和mPFC - GR的影响。CIE - ED组和ED组在饮酒期间CORT峰值升高。CIE - ED组和ED组在急性戒断期间mPFC - GR的表达和信号传导降低，全身米非司酮治疗可逆转这一效应。CIE - ED组和ED组在长期禁欲期间表现出强烈的乙醇寻求行为复现，且mPFC - GR表达增加。总体而言，数据表明CIE急性戒断会在GR信号传导、CORT和负面情绪症状方面产生强烈改变，这可能会促进过度饮酒。研究结果还表明，CIE - ED组和ED组表现出由乙醇线索引发的复吸易感性增强，这些变化部分由mPFC中GR表达改变介导。综上所述，向酒精依赖的转变可能伴随着mPFC应激相关途径的改变，这可能会增加负面情绪症状并增加复吸易感性。
