Munzar Patrik, Tanda Gianluigi, Justinova Zuzana, Goldberg Steven R
Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, NIDA, NIH, Department of Health and Human Services, Baltimore, MD 21224, USA.
Neuropsychopharmacology. 2004 Apr;29(4):705-17. doi: 10.1038/sj.npp.1300380.
Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did not increase brain dopamine levels when given alone. These findings point to histamine H3 receptors as a new and important receptor system modulating the reinforcing, subjective, and neurochemical actions of methamphetamine.
给予甲基苯丙胺会增加大脑中组胺的水平，而神经元组胺会减弱甲基苯丙胺的几种行为效应。然而，组胺受体不同亚型在这种负反馈中的作用仍不清楚。有一些证据表明组胺H3受体可能参与甲基苯丙胺的这些作用。本研究的目的是利用三种体内方法——药物自身给药、药物辨别和微透析，在斯普拉格-道利大鼠中评估两种组胺H3受体拮抗剂氯苯丙醇和硫代哌啶对甲基苯丙胺的奖赏和神经化学效应的影响。在按固定比率静脉注射甲基苯丙胺的大鼠中，硫代哌啶（1.0 - 3.0毫克/千克，皮下注射，s.c.）或氯苯丙醇（1.0 - 3.0毫克/千克，s.c.）的给药前治疗增强了甲基苯丙胺的强化作用，这表现为对低剂量0.03毫克/千克甲基苯丙胺的反应呈剂量依赖性增加，该剂量本身无法使反应维持在高于生理盐水替代水平，以及对较高剂量0.06毫克/千克训练剂量的甲基苯丙胺的反应减少。相比之下，硫代哌啶和氯苯丙醇治疗均未增加生理盐水替代期间的反应。在其他经训练能辨别腹腔注射（i.p.）1.0毫克/千克甲基苯丙胺和腹腔注射生理盐水的大鼠中，当与低剂量0.3毫克/千克腹腔注射的甲基苯丙胺一起给药时，硫代哌啶和氯苯丙醇（0.3 - 3.0毫克/千克，皮下注射）均剂量依赖性地增加了与甲基苯丙胺相符的反应，该剂量本身主要产生与生理盐水相符的反应。然而，当与生理盐水载体一起给药时，硫代哌啶和氯苯丙醇仅产生与生理盐水相符的反应。最后，硫代哌啶和氯苯丙醇增强了甲基苯丙胺诱导的伏隔核壳外细胞多巴胺水平的升高，但单独给药时并未增加脑内多巴胺水平。这些发现表明组胺H3受体是调节甲基苯丙胺的强化、主观和神经化学作用的一个新的重要受体系统。
