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Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice
Pharmacology Biochemistry and Behavior ( IF 3.3 ) Pub Date : 2021-08-19 , DOI: 10.1016/j.pbb.2021.173257
Nobue Kitanaka 1 , F Scott Hall 2 , Shotaro Kobori 1 , Sota Kushihara 1 , Hiroyuki Oyama 1 , Yasuki Sasaoka 1 , Megumi Takechi 1 , Koh-Ichi Tanaka 3 , Kazuo Tomita 4 , Kento Igarashi 4 , Nobuyoshi Nishiyama 3 , Tomoaki Sato 4 , George R Uhl 5 , Junichi Kitanaka 1
Affiliation  

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.



中文翻译:

Metoprine 是一种组胺 N-甲基转移酶抑制剂,通过激活小鼠的组胺能神经传递来减弱甲基苯丙胺诱导的过度运动

美托品通过抑制组胺N增加脑内组胺含量-甲基转移酶(HMT),一种中枢作用的组胺降解酶。我们提供的数据表明,使用旨在监测四种行为结果 [水平运动、食欲行为(食物获取)以及食物和水摄入] 的多配置行为装置,使用美托品预处理可减弱 METH 在小鼠中的超运动效应。美托品预处理本身在大部分光照阶段诱导用盐水攻击的小鼠的过度运动。在接下来的黑暗阶段也观察到了这种趋势。这是第一份关于美托品具有长效运动刺激特性的报道。同样,在悬尾试验中,单次注射美托品可显着减少小鼠的总不动时间,这与美托品具有运动刺激特性的观点一致。美托品预处理不影响行为的其他方面。美托品不影响食欲和饮酒行为,但对刻板印象有影响。在先用载体再用 METH 预处理的小鼠中没有观察到刻板行为,而在用美托品预处理然后用 METH 预处理的小鼠中观察到刻板的嗅探。在光相的前 2 小时内,甲氧托林预处理减弱了 METH 诱导的过度运动,这表明甲氧托林诱导的运动刺激特性可能与 METH 不同。服用甲托普林或 METH 后,组胺(但不是其脑代谢物)的下丘脑含量增加。METH 和甲氧托林分别降低了纹状体、伏隔核和下丘脑中的多巴胺和组胺转换,并且在组胺转换中存在显着的甲托品预处理 x METH 挑战相互作用。Metoprine 可能通过激活组胺能神经传递来减弱 METH 诱导的运动过度。Metoprine 还可能通过与 METH 诱导运动刺激作用不同的假定机制诱导持久的运动刺激作用。

更新日期:2021-09-03
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