Author: Ozawa, Rena ; Hall, F Scott ; Amatsu, Yukie ; Mimura, Mari ; Hisatomi, Erina ; Sato, Miho ; Uhl, George R ; Tagami, Kenta ; Takemura, Motohiko ; Kitao, Eri ; Hashimoto, Kotaku ; Nakamura, Miyu ; Kitanaka, Junichi ; Kitanaka, Nobue

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H₃ receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H₃ receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H₁ receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H₁ receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H₂ receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H₄ receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H₃ receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H₃ receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H₃ receptors, which then bind to the post-synaptic histamine receptor H₁ (but not H₂ or H₄). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.

01 Jul 2017·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice

Q3 · BIOLOGY

Article

Author: Mogi, Asuka ; Matsuzawa, Takuro ; Yoshikawa, Takeo ; Nakamura, Tadaho ; Kitano, Haruna ; Kárpáti, Anikó ; Yanai, Kazuhiko ; Naganuma, Fumito ; Harada, Ryuichi ; Iida, Tomomitsu

Brain histamine acts as a neurotransmitter and regulates various physiological functions, such as learning and memory, sleep-wake cycles, and appetite regulation. We have recently shown that histamine H3 receptor (H3R) is expressed in primary mouse microglia and has a strong influence on critical functions in microglia, including chemotaxis, phagocytosis, and cytokine secretion in vitro. However, the importance of H3R in microglial activity in vivo remains unknown. Here, we examined the effects of JNJ10181457 (JNJ), a selective and potent H3R inverse agonist, on microglial functions ex vivo and in vivo. First, we injected ATP, which is a typical chemoattractant, into hippocampal slices to investigate the effect of JNJ on chemotaxis. ATP-induced microglial migration toward the injected site was significantly suppressed by JNJ treatment. Next, we examined whether JNJ affected microglial phagocytosis in hippocampal slices and in the prefrontal cortex. Microglial engulfment of dead neurons induced by N-methyl-_d-aspartate was inhibited in the presence of JNJ. The increase in zymosan particle uptake by activated microglia in the prefrontal cortex was prevented by JNJ administration. Finally, we determined the importance of JNJ in a lipopolysaccharide (LPS)-induced depression model. JNJ reduced the LPS-induced upregulation of microglial pro-inflammatory cytokines and improved depression-like behaviour in the tail-suspension test. These results demonstrate the inhibitory effects of JNJ on chemotaxis, phagocytosis, and cytokine production in microglia inside the brain, and highlight the importance of microglial H3R for brain homeostasis.

01 Jun 2014·NeuropharmacologyQ2 · MEDICINE

Mechanism of the histamine H3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice

Q2 · MEDICINE

Article

Author: Watanabe, Takehiko ; Okamura, Nobuyuki ; Yoshikawa, Takeo ; Nakamura, Tadaho ; Yanai, Kazuhiko ; Miura, Yamato ; Mohsen, Attayeb ; Harada, Ryuichi ; Shibuya, Katsuhiko ; Iida, Tomomitsu ; Naganuma, Fumito

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Neurocognitive Disorders	Preclinical	US	Johnson & Johnson	-

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