Department of Psychology, Washington State University, Pullman, WA 99164, USA.
Department of Integrative Physiology & Neuroscience, Washington State University, Pullman, WA 99164, USA.
Neuropharmacology. 2017 Sep 15;124:121-133. doi: 10.1016/j.neuropharm.2017.05.023. Epub 2017 May 26.
Alcohol dependence is associated with anxiety during withdrawal. The endocannabinoid (ECB) system participates in the neuroendocrine and behavioral response to stress and changes in corticolimbic ECB signaling may contribute to alcohol withdrawal-induced anxiety. Moreover, symptoms of alcohol withdrawal differ between sexes and sexual dimorphism in withdrawal-induced ECB recruitment may be a contributing factor. Herein, we exposed intact male and female rats and ovariectomized (OVX) female rats with or without estradiol (E) replacement to 6 weeks of chronic intermittent alcohol vapor and measured anxiety-like behavior, ECB content, and ECB-related mRNA in the basolateral amygdala (BLA) and ventromedial prefrontal cortex (vmPFC). Acute alcohol withdrawal increased anxiety-like behavior, produced widespread disturbances in ECB-related mRNA, and reduced anandamide (AEA) content in the BLA and 2-arachidonoylglycerol (2-AG) content in the vmPFC of male, but not female rats. Similar to males, alcohol-exposed OVX females showed reductions in Napepld mRNA in the BLA, decreased AEA content in the BLA and vmPFC, and reductions in all ECB-related genes measured in the vmPFC. Importantly, E replacement prevented withdrawal-induced alterations in ECB content (but not mRNA) in OVX females, and although alcohol-exposed OVX females failed to exhibit more anxiety compared to their respective control, chronic alcohol exposure abolished the anxiolytic properties of E in OVX rats. These data indicate that ovarian sex hormones (but not E alone) protect against withdrawal-induced alterations in corticolimbic ECB signaling but do not impart resilience to withdrawal-induced anxiety. Thus, the mechanisms implicated in the manifestation of alcohol withdrawal-induced anxiety are most likely sex-specific. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
酒精依赖与戒断时的焦虑有关。内源性大麻素 (ECB) 系统参与神经内分泌和应激反应，皮质边缘 ECB 信号的变化可能导致酒精戒断引起的焦虑。此外，酒精戒断症状在性别之间存在差异，戒断引起的 ECB 募集的性别二态性可能是一个促成因素。在此，我们将完整的雄性和雌性大鼠以及去卵巢（OVX）雌性大鼠暴露于慢性间歇性酒精蒸气中 6 周，并测量焦虑样行为、ECB 含量以及外侧杏仁核（BLA）和腹内侧前额叶皮层（vmPFC）中的 ECB 相关 mRNA。急性酒精戒断会增加焦虑样行为，广泛扰乱 ECB 相关 mRNA，并减少雄性大鼠 BLA 中的花生四烯酸乙醇酰胺（AEA）含量和 vmPFC 中的 2-花生四烯酸甘油（2-AG）含量，但不影响雌性大鼠。与雄性大鼠相似，暴露于酒精的 OVX 雌性大鼠 BLA 中的 Napepld mRNA 减少，BLA 和 vmPFC 中的 AEA 含量减少，vmPFC 中测量的所有 ECB 相关基因减少。重要的是，E 替代可防止 OVX 雌性大鼠戒断引起的 ECB 含量（但不是 mRNA）改变，尽管与各自的对照相比，暴露于酒精的 OVX 雌性大鼠并未表现出更多的焦虑，但慢性酒精暴露会使 OVX 大鼠中 E 的抗焦虑作用消失。这些数据表明，卵巢性激素（而不仅仅是 E）可防止皮质边缘 ECB 信号的戒断引起的改变，但不会赋予戒断引起的焦虑的弹性。因此，表现出酒精戒断引起的焦虑的机制很可能是性别特异性的。本文是“大麻素神经生物学的新曙光”特刊的一部分。
