title: Mechanism of the histamine H(3) receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice.
abstract: Histaminergic neurons are activated by histamine H(3) receptor (H(3)R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H(3)R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H(3)R-mediated behavioural changes using a specific H(3)R antagonist, JNJ-10181457 (JNJ). First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N(τ)-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines. Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by α-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H(3)R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H(1)R gene knockout mice but not in histamine H2 receptor (H(2)R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an H(1)R antagonist, and dominantly by zolantidine, an H(2)R antagonist. These results suggest that H(3)R blockade induces histamine release, activates H(2)R and elicits exploratory locomotor activity and anxiety-like behaviours.
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Attayeb
authors: A
authors: Mohsen
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan. Electronic address: tyoshikawa@med.tohoku.ac.jp.
authors: Takeo
authors: T
authors: Yoshikawa
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Yamato
authors: Y
authors: Miura
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Tadaho
authors: T
authors: Nakamura
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Fumito
authors: F
authors: Naganuma
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Katsuhiko
authors: K
authors: Shibuya
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Tomomitsu
authors: T
authors: Iida
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Ryuichi
authors: R
authors: Harada
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Nobuyuki
authors: N
authors: Okamura
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Takehiko
authors: T
authors: Watanabe
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.
authors: Kazuhiko
authors: K
authors: Yanai
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008761:Methylhistamines / Q000378:metabolism; D008762:Methylhistidines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000633:toxicity; D010880:Piperidines / Q000633:toxicity; D011969:Receptors, Histamine H1 / Q000172:deficiency / Q000235:genetics; D011970:Receptors, Histamine H2 / Q000172:deficiency / Q000235:genetics; D018100:Receptors, Histamine H3 / Q000502:physiology*
chemical_list: C515396:4-(3-(4-piperidin-1-ylbut-1-ynyl)benzyl)morpholine; D015306:Biogenic Monoamines; D004791:Enzyme Inhibitors; D006633:Histamine Antagonists; D008761:Methylhistamines; D008762:Methylhistidines; D009025:Morpholines; D010880:Piperidines; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; C028309:alpha-fluoromethylhistidine; D006632:Histamine
keywords: Anxiety-like behaviours; Brain histamine; Histamine H(3) receptor antagonists; Locomotor activity