Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Alcohol Clin Exp Res. 2019 Oct;43(10):2134-2143. doi: 10.1111/acer.14163. Epub 2019 Aug 23.
Chronic ethanol (EtOH) exposure induces neurobehavioral maladaptations in the brain though the precise changes have not been fully explored. The central nucleus of the amygdala (CEA) regulates anxiety-like behavior induced by withdrawal from chronic intermittent EtOH (CIE) exposure, and the arginine vasopressin (AVP) system within the CEA regulates many anxiety-like behaviors. Thus, adaptations occur in the CEA AVP system due to chronic EtOH exposure, which lead to anxiety-like behaviors in rats.
Chronic exposure to a low-dose EtOH (4.5% wt/vol) induces anxiety-like behavior in rats. Wistar or Sprague Dawley rats were exposed to a modified CIE or CIE, while intra-CEA microinjections of AVP or a V1b receptor antagonist were used to elicit or block withdrawal-induced anxiety. Additionally, AVP microinjections into the CEA were given 24 hours following 15 days of continuous high-dose EtOH (7% wt/vol), a time period when rats no longer express anxiety. Chemogenetics was also used to activate the basolateral amygdala (BLA) or deactivate the dorsal periaqueductal gray=(dm/dlPAG) therefore PAG=periaqueductal gray to elicit or block withdrawal-induced anxiety.
AVP microinjected into the CEA in lieu of exposure to the first 2 cycles of CIE was sufficient to induce anxiety-like behavior in these commonly used rat strains. The V1b receptor antagonist, but not an oxytocin receptor agonist, into the CEA during the first 2 withdrawal cycles suppressed anxiety. However, activation of the BLA in lieu of exposure to the first 2 cycles of CIE was insufficient to induce anxiety-like behavior. AVP microinjection into the CEA 24 hours into withdrawal reelicited anxiety-like behavior, and deactivation of the dm/dlPAG reduced this effect of CEA AVP.
Taken together, this study demonstrates a role of CEA AVP and a CEA-dm/dlPAG circuit in the development of anxiety induced by CIE. Such information is valuable for identifying novel therapeutic targets for alcohol- and anxiety-associated disorders.
慢性乙醇（EtOH）暴露会导致大脑的神经行为适应不良，尽管确切的变化尚未完全探索。杏仁中央核（CEA）调节慢性间歇性 EtOH（CIE）暴露戒断引起的类似焦虑的行为，而 CEA 内的精氨酸加压素（AVP）系统调节许多类似焦虑的行为。因此，由于慢性 EtOH 暴露，CEA AVP 系统会发生适应性变化，从而导致大鼠出现类似焦虑的行为。
慢性低剂量 EtOH（4.5%wt/vol）暴露会诱导大鼠出现类似焦虑的行为。Wistar 或 Sprague Dawley 大鼠接受改良的 CIE 或 CIE 暴露，同时在 CEA 内进行 AVP 或 V1b 受体拮抗剂的微注射，以引发或阻断戒断引起的焦虑。此外，在连续 15 天高剂量 EtOH（7%wt/vol）后 24 小时，将 AVP 微注射到 CEA 中，此时大鼠不再表现出焦虑。化学遗传学也被用于激活基底外侧杏仁核（BLA）或失活背侧中脑导水管周围灰质=（dm/dlPAG），从而引发或阻断戒断引起的焦虑。
在 CEA 中注射 AVP 以替代 CIE 的前 2 个周期的暴露足以在这些常用的大鼠品系中引起类似焦虑的行为。在 CIE 的前 2 个戒断周期中，将 V1b 受体拮抗剂而非催产素受体激动剂注射到 CEA 中，可抑制焦虑。然而，在 CIE 的前 2 个周期暴露替代下，激活 BLA 不足以引起类似焦虑的行为。在戒断后 24 小时将 AVP 微注射到 CEA 中会重新引起类似焦虑的行为，而 dm/dlPAG 的失活会减少 CEA AVP 的这种作用。
综上所述，这项研究表明 CEA AVP 和 CEA-dm/dlPAG 回路在 CIE 引起的焦虑发展中起作用。这些信息对于确定治疗酒精和焦虑相关障碍的新治疗靶点具有重要价值。
