Neuronal nitric oxide synthase alteration accounts for the role of 5-HT1A 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) 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.
Zhang
Jing
J
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.
Huang
Xin-Yan
XY
Ye
Min-Li
ML
Luo
Chun-Xia
CX
Wu
Hai-Yin
HY
Hu
Yao
Y
Zhou
Qi-Gang
QG
Wu
Dan-Lian
DL
Zhu
Li-Juan
LJ
Zhu
Dong-Ya
DY
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001008:Anxiety Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D050882:CREB-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D050882:CREB-Binding Protein; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D007191:Indazoles; D052248:Nitric Oxide Synthase Type I; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C080122:7-nitroindazole