Department of Psychopharmacology, Qiqihar Medical University, Qiqihar 161006, China.
Medical Research Center, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
Behav Neurol. 2021 Nov 29;2021:2149371. doi: 10.1155/2021/2149371. eCollection 2021.
Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28 day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW.
乙醇戒断（EtOHW）改变了神经激素和行为对外源和内源刺激的反应模式，这介导了即使在长时间戒酒后对酒精使用的复发。EtOHW 期间从孤束核（NTS）到终纹床核（BNST）的去甲肾上腺素能信号增加是戒断引起焦虑的基础，而一氧化氮合酶（NOS）抑制剂注入导水管周围灰质区域可减轻 EtOHW 引起的焦虑。因此，本研究在经历轻度应激的大鼠中，研究了 NTS 内 NOS 参与慢性 EtOHW 期间 BNST 中焦虑和去甲肾上腺素（NE）释放增加的情况。大鼠腹腔内每天给予 3g/kg EtOH 21 天，随后进行 28 天戒断，在戒断的第 28 天，大鼠接受 7 分钟的束缚应激。高架十字迷宫测试用于评估大鼠的焦虑样行为，而体内微透析用于测量 BNST 中的细胞外 NE 水平。在高架十字迷宫测试中，EtOHW 大鼠而非 EtOH 未处理大鼠在受到 7 分钟轻度束缚应激的挑战时表现出焦虑样行为，而预先在 NTS 内输注一氧化氮清除剂 2-（4-羧基苯基）-4,4,5,5-四甲基咪唑啉-1-氧-3-氧化物（羧基-PTIO）、非选择性 NOS 抑制剂 NG-硝基-L-精氨酸甲酯（L-NAME）或选择性神经元 NOS（nNOS）抑制剂 7-硝基吲唑（7-NI）分别减轻了这种行为，这些药物也降低了 EtOHW 大鼠的血浆皮质酮水平。在体内微透析中，预先在 NTS 内输注羧基-PTIO、L-NAME 或 7-NI 可减轻 EtOHW 大鼠在轻度应激刺激下 BNST 中 NE 的释放。此外，EtOHW 大鼠显示出孤立的 nNOS 基因和蛋白表达增加。此外，NTS 内给予 7-NI 的抗焦虑作用被随后的 NTS 内给予硝普钠所消除。这些结果表明，源自 nNOS 的孤立一氧化氮信号的升高介导了慢性 EtOHW 期间应激引起的 BNST 焦虑和去甲肾上腺素释放。
