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Objection Epidemiological studies of anxiety disorders have indicated that as many as 29% of people will, at some point in their lives, suffer from anxiety disorders.The serotonergic system is essential for regulating affects and moods, and has long been implicated in the pathogenesis of anxiety.The activity of serotonergic pathways is critically regulated by plasma membrane serotonin transporter and serotonin receptors.Among various 5-HT receptor subtypes, 5-HT1A receptors have been predominantly involved in anxiety-related behaviors.However, the mechanism underlying the role of 5-HT1A receptors in these diseases remains unknown.Results Here we show that 5-HT1A R-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine down-regulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT1AR-selective antagonist NAN-190 up-regulated 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 (KO) or treated with nNOS-selective inhibitor 7-NI (i.p., 30 mg/kg/d for 28 days, or intrahippocampal microinjection, 16.31 μg/1.0 μL) displayed an anxiolytic-like phenotype, implicating nNOS anxiety.We also show that, in wild-type (WT) mice, adminstrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 days caused anxiolytic-like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 days) 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-day 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 CREB levels in WT mice but not in KO mice.Blockade of hippocampal CREB phosphorylation by microinj ection of H89 (5.19 μg/1.0 μL), a PKA inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 days).Conclusin These findings indicate that hippocampal nNOS and CREB activity mediate the anxiolytie effects of 5-HT1AR agonists and SSRIs.