title: VEGF-induced antidepressant effects involve modulation of norepinephrine and serotonin systems.
abstract: Throughout life, we are exposed to a variety of stresses, which may be inevitable and noxious sometimes. During evolution, animals must have acquired some physiological means to counteract stress. Vascular endothelial growth factor (VEGF) is an angiogenic and neurogenic factor, which has been shown to elicit antidepressant-like effects in response to different external stimuli, potentially functioning as an anti-stress molecule. However, it remains largely unknown how VEGF modulates mood-related behaviors. To investigate molecular correlates, we analyzed monoaminergic systems of VEGF transgenic mice that display antidepressant-like behavior. Immunostaining showed that overall morphologies of monoaminergic nuclei and their processes were normal. However, we found imbalances in brain monoamine contents, in which the levels of norepinephrine and serotonin, but not dopamine, were decreased exclusively in the regions where VEGF was expressed. The turnover of norepinephrine showed a marked increase and serotonin turnover showed a modest reduction, whereas dopamine turnover was not affected. The protein levels of tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes of catecholamine and serotonin synthesis, remained constant. The mRNA levels of monoamine receptors were generally similar but adrenergic receptors of ADRα1A and ADRβ1 were down-regulated. Behavioral tests showed that serotonin- or norepinephrine-selective antidepressant drugs failed to additively enhance antidepressant-like behaviors, whereas monoamine depleting drugs attenuated VEGF-mediated antidepressant-like effect. These data suggest that VEGF-induced antidepressant-like effects involve modulation of norepinephrine and serotonin systems.
authors.affiliation: Department of Biology, Graduate School of Science, Kyushu University, Fukuoka 812-8581, Japan. Electronic address: hudouscb@kyushu-u.org.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Udo
authors.affiliation: Laboratory of Regulation in Metabolism and Behavior, Graduate School of Bioresource and Bioenvironmental Science, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Hamasu
authors.affiliation: Laboratory of Regulation in Metabolism and Behavior, Graduate School of Bioresource and Bioenvironmental Science, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Furuse
authors.affiliation: Department of Biology, Graduate School of Science, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003863:Depression / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity; D010134:Fenclonine / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013550:Swimming / Q000523:psychology; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D019805:alpha-Methyltyrosine / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D042461:Vascular Endothelial Growth Factor A; D012701:Serotonin; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D010134:Fenclonine; D009638:Norepinephrine
keywords: Behavior; Depression; Mice; Monoamine; VEGF