Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.
J Neurosci. 2010 Feb 17;30(7):2433-41. doi: 10.1523/JNEUROSCI.5880-09.2010.
Increasing evidence suggests that 5-HT(1A) receptor (5-HT(1A)R) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT(1A)R in these diseases remains unknown. Here, we show that 5-HT(1A)R-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT(1A)R-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 microg/1.0 microl) 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 microg/100 microl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 microg/1.0 microl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 microg/1.0 microl). 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 microg/1.0 microl), 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-HT(1A)R agonists and SSRIs.
越来越多的证据表明，5-羟色胺（1A）受体（5-HT（1A）R）与焦虑障碍有关。然而，5-HT（1A）R 在这些疾病中的作用机制尚不清楚。在这里，我们显示 5-HT（1A）R 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型一氧化氮合酶（nNOS）表达，而 5-HT（1A）R 选择性拮抗剂 NAN-190 上调海马 nNOS 表达。通过使用新异抑制进食、旷场和高架十字迷宫测试评估焦虑相关行为，我们显示缺乏 nNOS 基因的小鼠[敲除（KO）]或用 nNOS 选择性抑制剂 7-硝基吲唑（7-NI；腹腔内，30 mg/kg/d，持续 28 天；或海马内微量注射，16.31 μg/1.0 μl）处理显示出焦虑样表型，表明 nNOS 与焦虑有关。我们还显示，在野生型（WT）小鼠中，28 天腹腔内给予 8-OH-DPAT（0.1 mg/kg/d）或氟西汀（10 mg/kg/d）可产生抗焦虑样作用，而 NAN-190（腹腔内，0.3 mg/kg/d，持续 28 天）可产生焦虑样作用。然而，在 KO 小鼠中，这些药物无效。此外，使用 14 天渗透压微量泵在海马内输注 8-OH-DPAT（45.963 μg/100 μl）可产生抗焦虑作用。海马内微量注射 7-NI（16.31 μg/1.0 μl）消除了海马内 NAN-190（4.74 μg/1.0 μl）的焦虑样作用。此外，NAN-190 降低 WT 小鼠而不降低 KO 小鼠中海马磷酸化 cAMP 反应元件结合蛋白（CREB）水平，而 8-OH-DPAT 增加。微注射 PKA（蛋白激酶 A）抑制剂 H89（5.19 μg/1.0 μl）阻断海马 CREB 磷酸化，消除 7-NI（腹腔内，30 mg/kg/d，持续 21 天）的抗焦虑作用。这些发现表明，海马 nNOS 和 CREB 活性均介导 5-HT（1A）R 激动剂和 SSRIs 的抗焦虑作用。
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