Department of Psychopharmacology, School of Mental Health, Qiqihar Medical University, 333 Bukuibei Street, Jianhua District, Qiqihar, 161006, China.
College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.
BMC Complement Altern Med. 2019 Jun 24;19(1):147. doi: 10.1186/s12906-019-2546-0.
Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways.
Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays.
MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS.
These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.
乙醇戒断（EtOHW）焦虑是酒精复发的一个关键风险因素。神经肽孤啡肽/孤啡肽 FQ（N/OFQ）通过其受体（NOP）发挥作用，拮抗促肾上腺皮质激素释放因子（CRF）并产生抗焦虑作用。酸枣仁（SZS）是东方医学中的一种典型的催眠镇静草药，在尼古丁戒断期间通过改善杏仁核 CRF/CRFR1 信号来表现出抗焦虑作用。因此，我们评估了 SZS 对 EtOHW 焦虑的影响，以及杏仁核 CRF/CRFR1 和 N/OFQ/NOP 途径的参与情况。
雄性 Sprague Dawley 大鼠每天接受腹腔注射 2g/kg EtOH（20% v/v），共 28 天，然后进行 3 天的戒断。在 EtOHW 期间，大鼠每天给予甲醇提取物 SZS（MESZS，60 或 180mg/kg/d）一次胃内治疗。通过旷场（OF）和高架十字迷宫（EPM）测试测量焦虑样行为，通过酶联免疫吸附测定法检查血浆皮质酮（CORT）水平。通过定量聚合酶链反应和 Western blot 测定测定神经肽及其受体的 mRNA 和蛋白表达水平。
MESZS 增加了 EtOHW 大鼠在 OF 中心区域的行进距离，并剂量依赖性地延长了其在中心区域的停留时间。MESZS 增加了 EtOHW 大鼠进入和停留在 EPM 开放臂的次数和时间。此外，MESZS 抑制了 EtOHW 期间血浆 CORT 的过度分泌。EtOHW 增强了杏仁核中央核（CeA）中的 CRF 和 CRFR1 基因和蛋白表达，这一作用被 180mg/kg/d MESZS 抑制。EtOHW 增加了杏仁核 NOP mRNA 和蛋白表达，但不影响 N/OFQ mRNA 表达，而 180mg/kg/d MESZS 进一步促进了这些增加。此外，CeA 内给予 CRF 或选择性 NOP 拮抗剂 UFP-101 后，180mg/kg/d MESZS 的预期抗焦虑作用被消除。
这些结果表明，MESZS 通过改善 CeA 中的 CRF/CRFR1 和 N/OFQ/NOP 传递来改善 EtOHW 焦虑。
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