Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT1A Receptor in Modulating Anxiety-Related Behaviors
Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT1A Receptor in Modulating Anxiety-Related Behaviors
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DOI：
10.1523/jneurosci.5880-09.2010
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发表时间：
2010-02-17
影响因子：
5.3
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
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作者：
Zhang, Jing;Huang, Xin-Yan;Zhu, Dong-Ya
越来越多的证据表明 5-HT1A 受体 (5-HT1AR) 与焦虑症有关。然而，5-HT1AR 在这些疾病中的作用机制仍不清楚。在这里，我们发现5-HT1AR选择性激动剂8-OH-DPAT和选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀下调海马神经元一氧化氮合酶（nNOS）表达，而5-HT1AR选择性拮抗剂NAN-190上调海马nNOS表达。通过使用新奇抑制进食、旷场和高架十字迷宫测试评估焦虑相关行为，我们发现缺乏 nNOS 基因[敲除（KO）]或用 nNOS 选择性抑制剂 7-硝基吲唑（7-NI；腹腔注射，30 mg/kg/d，持续 28 天；或海马内微量注射，16.31 μg/1.0 μl）治疗的小鼠表现出焦虑相关行为。抗焦虑样表型，表明 nNOS 与焦虑有关。我们还表明，在野生型（WT）小鼠中，连续28天给予8-OH-DPAT（腹腔注射，0.1 mg/kg/d）或氟西汀（腹腔注射，10 mg/kg/d）会引起抗焦虑样作用，而NAN-190（腹腔注射，0.3 mg/kg/d，28天）会引起类焦虑样作用。然而，在 KO 小鼠中，这些药物无效。此外，使用14天渗透微型泵向海马内输注8-OH-DPAT（45.963μg/100μl）产生抗焦虑作用。海马内显微注射7-NI（16.31μg/1.0μl）消除了海马内NAN-190（4.74μg/1.0μl）的类焦虑作用。此外，在 WT 小鼠中，NAN-190 降低，8-OH-DPAT 增加磷酸化 cAMP 反应元件结合蛋白 (CREB) 水平，但在 KO 小鼠中则不然。通过显微注射 H89（5.19 μg/1.0 μl）（一种 PKA（蛋白激酶 A）抑制剂）阻断海马 CREB 磷酸化，消除了 7-NI（腹腔注射，30 mg/kg/d，持续 21 天）的抗焦虑样作用。这些发现表明海马 nNOS 和 CREB 活性介导 5-HT1AR 激动剂和 SSRI 的抗焦虑作用。
Increasing evidence suggests that 5-HT1A receptor (5-HT1AR) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT1AR in these diseases remains unknown. Here, we show that 5-HT1AR-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT1AR-selective antagonist NAN-190 upregulated hippocampal nNOS expression. By assessing anxiety-related behaviors using the novelty suppressed feeding, open-field, and elevated plus maze tests, we show that mice lacking nNOS gene [knock-out (KO)] or treated with nNOS-selective inhibitor 7-nitroindazole (7-NI; i.p., 30 mg/kg/d for 28 d; or intrahippocampal microinjection, 16.31 mu g/1.0 mu l) displayed an anxiolytic-like phenotype, implicating nNOS in anxiety. We also show that, in wild-type (WT) mice, administrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 d caused anxiolytic-like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 d) caused anxiogenic-like effects. In KO mice, however, these drugs were ineffective. Moreover, intrahippocampal infusion of 8-OH-DPAT (45.963 mu g/100 mu l) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 mu g/1.0 mu l) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 mu g/1.0 mu l). Additionally, NAN-190 decreased and 8-OH-DPAT increased phosphorylated cAMP response element-binding protein (CREB) levels in WT mice but not in KO mice. Blockade of hippocampal CREB phosphorylation by microinjection of H89 (5.19 mu g/1.0 mu l), a PKA (protein kinase A) inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 d). These findings indicate that both hippocampal nNOS and CREB activity mediate the anxiolytic effects of 5-HT1AR agonists and SSRIs.