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Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT 1A Receptor in Modulating Anxiety-Related Behaviors
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) flu...
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Published in: | The Journal of neuroscience 2010-02, Vol.30 (7), p.2433-2441 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 μg/1.0 μl) 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 μg/100 μl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 μg/1.0 μl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 μg/1.0 μl). 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 μg/1.0 μl), 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. |
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ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/JNEUROSCI.5880-09.2010 |