Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT1A Receptor in Modulating Anxiety-Related Behaviors

• Published in: The Journal of neuroscience 2010-02, Vol.30 (7), p.2433-2441
• Main Authors: Zhang, Jing, Huang, Xin-Yan, Ye, Min-Li, Luo, Chun-Xia, Wu, Hai-Yin, Hu, Yao, Zhou, Qi-Gang, Wu, Dan-Lian, Zhu, Li-Juan, Zhu, Dong-Ya
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; Animals, Newborn; Anxiety Disorders - chemically induced; Anxiety Disorders - drug therapy; Anxiety Disorders - enzymology; Anxiety Disorders - physiopathology; CREB-Binding Protein - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Exploratory Behavior - drug effects; Feeding Behavior - drug effects; Fluoxetine - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; Indazoles - pharmacology; Male; Maze Learning - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type I - deficiency; Nitric Oxide Synthase Type I - physiology; Phosphorylation - drug effects; Piperazines - therapeutic use; Reaction Time - drug effects; Receptor, Serotonin, 5-HT1A - physiology; Serotonin Antagonists - therapeutic use; Serotonin Receptor Agonists - pharmacology; Serotonin Uptake Inhibitors - pharmacology; Time Factors
• ISSN: 0270-6474; 1529-2401
• 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.