组胺酸脱羧酶基因敲除小鼠学习记忆和海马CA1区突触可塑性的改变
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摘要
组胺是体内广泛存在的自体活性物质和炎症介质，在20世纪80年代两个研究组同时用免疫组织化学的方法证实了组胺能神经元主要分布在下丘脑，组胺在中枢神经系统中的作用才逐渐为人们所承认和重视。目前认为脑内组胺能神经元广泛分布于下丘脑的结节乳头核(nucleus tuberomammillaris，TM)，而且TM是脑内组胺能神经元分布的唯一区域，但其轴突可以投射到脑内的绝大部分区域，包括丘脑、杏仁核、海马结构、大脑皮层等。组胺在脑内由其前体组胺酸(L-histidine)脱羧生成，组胺酸脱羧酶(histidine decarboxylase，HDC)是目前发现的唯一组胺合成酶。在中枢神经系统，组胺有三种受体(H1、H2、H3)，均已得到分离鉴定，它们属于G蛋白偶联受体超家族，具有七个跨膜区域。H1受体与磷脂酶C(phospholipase C)、蛋白激酶C(protein kinase C)藕联，H2受体与cAMP、蛋白激酶A(protein kinase A)耦联。H3受体与Gi／Go藕联，是突触前自身受体，对组胺的释放有抑制作用，也影响组胺的合成。同时，它也是异源性受体，在黑质纹状体、杏仁核、大脑皮层等区域调节其它递质的释放。总体上，H1和H2受体对神经元起兴奋性作用，或增强其兴奋性传入。相反，H3受体激活对TM神经元产生负反馈抑制，并能抑制神经递质的释放。
组胺作为神经系统的递质或调质，在许多中枢活动中起着重要的调节作用，如神经内分泌调节、饮水摄食调节、体温调节、觉醒—睡眠、运动、攻击行为以及学习记忆等。学习记忆是脑的高级功能，在许多发病率较高的中枢神经系统疾病中，病人的学习记忆功能均受到不同程度的损害。因此，组胺与学习记忆的关系成为越来越多的研究者致力的热点问题。但随着研究的深入，人们发现组胺系统对学习记忆的影响十分复杂，对组胺以及组胺系统的相关药物在行为学方面的研究均出现不一致的结果。其中较为重要的原因是，组胺系统的药理学工具特异性相对较低，并没有选择性的、能够显著持久的抑制脑内组胺合成，及同时拮抗所有组胺受体的工具药。因此，越来越多的研究者采用HDC基因敲除(HDC-KO)小鼠来探讨组胺长期缺乏后对学习记忆的影响。研究表明，HDC-KO小鼠对物体的辨别记忆能力较其野生型(wild type，WT)小鼠下降，而在水迷宫和被动回避反应的学习记忆能力增强，并认为其与多巴胺的负性增强有关。但是这种假设需要在其它学习记忆模型中进一步证明，同时这些研究均停留在行为学水平，没有探讨其增强效应的深入机制。由于背景和空间学习记忆与海马结构的突触可塑性密切相关，在组胺的长期缺乏的情况下是否影响HDC-KO小鼠的海马的突触可塑性，而且在学习记忆的行为学任务中，这种突触可塑性是否发生改变，如何改变，至今仍不清楚。
因此为了进一步研究组胺长期缺乏对学习记忆的影响及其深入机制，本研究采用海马依赖的背景恐惧记忆模型，观察HDC-KO小鼠的学习记忆改变；同时用细胞外电生理记录HDC-KO小鼠突触可塑性的改变，探讨行为学改变的生理机制。
第一部分HDC基因敲除小鼠背景恐惧记忆的改变
近年来，恐惧条件反射模型(Pavlovian fear conditioning)逐渐成为研究学习记忆神经生物学机制的主要行为学模型，分为背景恐惧条件反射(cntextual fearconditioning)和线索恐惧条件反射(cued fear conditioning)。在这个模型中，小鼠需要在训练中将仪器背景刺激及声音刺激(conditioned stimulus)和足底电刺激(unconditioned stimulus)联系起来，产生对背景或声音的恐惧记忆，当小鼠再次暴露到相同背景或者在不同背景中的声音刺激时，小鼠会表现出呆滞反应(freezing)，其持续时间的长短是衡量恐惧记忆能力的标志。背景恐惧记忆而不是线索恐惧记忆依赖于海马。为了进一步研究组胺长期缺乏在海马依赖的学习记忆的重要作用，我们采用背景恐惧条件反射模型，观察HDC-KO小鼠的学习记忆是否发生改变。RT-PCR和高效液相结果显示HDC-KO小鼠不含有HDC基因，而且体内组胺含量极低。免疫印记发现HDC-KO小鼠海马细胞膜H2受体上调。行为学结果显示，给予电刺激后，HDC-KO小鼠的呆滞反应时间百分率从2h开始较WT小鼠升高，至训练后1d有显著性升高，并且一直持续到训练后14d。这些结果提示HDC-KO小鼠对背景恐惧记忆较WT小鼠显著增强，其时程的改变提示组胺长期缺乏可能参与海马的获得和巩固。我们进一步在训练前、训练后以及测试前脑室内注射组胺来确定背景恐惧记忆的增强，同时探讨组胺的缺乏将影响获得、巩固和再现中的哪个过程。结果发现，在训练前、训练后注射组胺明显降低HDC-KO小鼠呆滞反应的时间百分率，在测试前注射没有影响，证明组胺长期缺乏可能影响了海马的获得和巩固过程，对再现过程没有影响。对线索恐惧记忆的结果表明，HDC-KO小鼠在未受电击的环境中受到声音刺激时，其呆滞反应时间也延长，提示组胺长期缺乏导致的学习记忆增强对海马的依赖可能不是特异性的。
第二部分HDC基因敲除小鼠的突触可塑性改变
海马在学习记忆过程中突触可塑性的形成重要作用，海马的长时程增强(Long-term potentiation，LTP)是研究的最为广泛的活性依赖的突触可塑性的模型，被认为是学习记忆的神经基础。海马齿状回、CA3、CA1均有习得性长时程增强的突触效应，其中以Schaffer侧支与CA1形成的通路与空间背景学习记忆关系最为密切。在第一部分中，我们已经发现组胺的长期缺乏增强HDC-KO小鼠的背景学习记忆，并影响获得和巩固过程。在本部分实验中，主要研究行为学改变的突触可塑性机制。细胞外电生理结果显示，HDC-KO小鼠的基本输入输出曲线(input-output curve)较WT小鼠没有明显改变，即CA1区的基本突触传递并没有因为敲除HDC基因而改变；在TBS刺激后HDC-KO小鼠的群峰电位增强的幅度明显高于WT小鼠，即HDC-KO小鼠的LTP较WT小鼠显著增强，并可以持续2h直到记录结束；10μM组胺灌流小鼠海马脑片，给予TBS刺激诱导LTP后，其幅度明显下降，说明HDC-KO小鼠LTP的增强是由组胺的长期缺乏特异性引起的；HDC-KO小鼠的双脉冲易化在LTP诱导前后有明显差异，特别是诱导后较WT小鼠显著下降，提示在LTP诱导后，HDC-KO小鼠的突触前谷氨酸释放增加，参与了LTP的增强效应；而在训练后1d时，两种基因型小鼠的LTP较正常时均明显下降，但WT小鼠的LTP幅度反而明显高于HDC-KO小鼠的LTP，提示HDC-KO小鼠的背景恐惧记忆明显增强时，突触传递已经维持在较高的水平，LTP出现饱和现象，进一步证明其行为学的改变，以及LTP与联合性学习记忆的相关性。
总结
1．内源性组胺长期缺乏导致背景恐惧记忆增强，这种增强作用从训练后2h开始，一直持续到14d。组胺脑室内注射提示，组胺长期缺乏对海马的获得和巩固过程有明显影响。HDC-KO小鼠对声音的恐惧记忆亦增强，提示组胺长期缺乏对背景恐惧记忆的影响并不是特异性的，其不仅对海马的功能有影响，也可能影响杏仁核的功能。
2．两种基因型小鼠海马脑片的电生理记录显示，虽然HDC-KO小鼠的输入输出曲线左移，但与WT对照小鼠比较没有显著性差异，提示HDC-KO小鼠的基本电生理特性没有发生明显改变；内源性组胺长期缺乏导致HDC-KO小鼠海马脑片CA1区LTP增强，而LTD没有发生明显变化；LTP诱导前和诱导后的PPF下降，以及生化结果发现行为学训练后1d和4d海马内谷氨酸含量增加，提示突触前谷氨酸释放增加可能参与背景恐惧记忆和LTP的增强效应；
3．HDC-KO小鼠训练后1d海马脑片电生理记录显示，LTP幅度较WT小鼠明显降低，提示训练后1d背景恐惧增强时其突触效能已经明显增强，LTP与联合性学习记忆的密切相关。
4．本研究进一步阐明HDC-KO小鼠对海马依赖的背景恐惧记忆影响，并首次揭示了本实验和以往实验中学习记忆改变的机制，即内源性组胺长期缺乏可能导致海马CA1区突触传递的增强，对比以往局限于外源性组胺的研究，我们的结果从相反的角度深化了组胺与突触可塑性关系的认识，为今后组胺在学习记忆方面的基础和临床研究提供了新的思路。
Histamine is one of the most widely distributed inflammatory substances in the body. Compared with other aminergic systems, the histaminergic system in the CNS gained general acceptance only in 1984, after the immunohistochemical demonstration that the tuberomamillary (TM) nucleus was the sole seat of histaminergic neurons and the origin of the widely distributed histaminergic projections. It is now thought that their efferent fibers project to almost the entire brain, including the hypothalamus, septum, thalamus, cortex, amygdala, and hippocampus. Histamine is synthesised in brain from L-histidine by the enzyme histidine decarboxylase (HDC), and up to now HDC is the only enzyme catalyzed the process. Four histamine receptors have been cloned (H1-H4), and the H1, H2 and H3 histamine receptors are all expressed in distinctive patterns in the brain. The H1 receptor is a 486-491 amino acid protein encoded by an intronless gene, and is coupled to the Gq/11 protein and phospholipase C. The H2 receptor is coupled to Gs and protein kinase A and the protein consists of 358-359 amino acids. The H3 autoreceptor is coupled to Gi/Go, displays a significant constitutive activity, and controls histamine release and synthesis. The H3 receptor regulates the release of several transmitters in brain areas, such as the substantia nigra, amygdala and cerebral cortex.
Histamine controls a variety of neurobiological functions and behavioral responses including sleep-wake cycle, water consumption, food, motor activity, and nociception. Histamine is also involved in learning and memory, and many researchers have contributed a lot in this field. However, these studies yielded to contradictory results. For instance, histamine improved and impaired active avoidance conditioning. The HDC-blocker α-iluoromethylhistidine (α-FMH) also has those effects in a radial-maze task. Furthermore, H_1 receptor antagonism has different influence on spatial memory performance and some emotional tasks. There were also discrepancies found with H_2 receptor antagonists and agonists and H3 receptor. The mechanisms underlying these differences seem to be very complex, which may be in part due to the methods used and the approaches selected in the experiments. Most histaminergic agents, and lesions of the TM and hippocampus, not only influence the histaminergic system but also affect non-histaminergic systems in the brain. So, recently histidine decarboxylase knockout (HDC-KO) mice have been developed to study the role of the histaminergic system in learning and other behaviors more specifically and to explain these discrepancies. Previous research showed that HDC-KO mice had improved water maze performance during both hidden and cued platform tasks, but exhibit deficient object discrimination based on temporal relationships. It is proposed that disruption of brain histamine synthesis may actually have bidirectional effects on learning and memory related to the reinforcement contingencies inherent in the task. However, this hypothesis needs further confirmation. Furthermore, these studies have not explained the mechanisms of the enhancement of learning and memory in the behavioral tasks. Contextual and spatial learning and memory is closely related to the synaptic plasiticity, and it is still unclear whether long-term histamine deficiency influences the synaptic plasiticity during the behavioral performance in HDC-KO mice.
In the present study, we investigated the change of learning and memory in hippocampal-dependent contextual fear conditioning, and the synaptic plasiticity in hippocampal CA1 region using electrophysiological recording to explain the mechanisms of behavioral performance in HDC-KO mice.
Part I Contextual fear conditioning in HDC-KO mice
Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. It can be divided into contextual fear conditioning and cued fear conditioning according to the conditioned sitmulus. Contextual but not cued fear memory is dependent on the hippocampus. In this paradigm, mice were given the opportunity to associate both a tone (cue) and the apparatus (context) with footshock in a single training trial. Memory was assessed by scoring the percent time mice spent immobile (freezing, a fear reaction) upon reexposure either to the context or the cue in a distinct context. In this part of investigation, we used contextual fear conditioning to examine learning and memory ability in HDC-KO mice. The data showed that mice lacking histamine exhibited improved contextual fear memory, and this improvement was maintained for a long period from 2h to 14d. The intracerebroventricular injection of histamine before and immediately after training reversed the improvement, while the injection before testing had on effects. HDC-KO mice also showed enhancement of cued fear compared with the wildtype (WT) mice. The results indicated that contextual fear memory increased in HDC-KO mice from 2h to 14d after training, and long-term histamine deficiency may upregulate hippocampal acquisition and consolidation of contextual fear. While these influences may be not specific to the hippocampus, amygdala may also be involved in the process. Part II synaptic plasiticity in the hippocampal CA1 region in
HDC-KO mice
Hippocampus plays an important role in synaptic plasiticity. Physiologial activity-dependent long-term changes in synaptic transmission, as long-term potentiation (LTP) are thought to be the substrate of learning and memory. Contextual and spatial learning and memory are closely related to the LTP in the synapse from the Schaffer collateral pathway to CA1 cells. We found that long-term histamine deficiency increased the acquisition and consolidation of contextual fear in HDC-KO mice. In this part, we investigated the synaptic plasiticity in hippocampal CA1 region to explain the behavioral performance in HDC-KO mice. The data showed that there was no difference in input-out curve and LTD between the two genotypes. While under normal conditions, LTP was stronger in HDC-KO mice than that in WT mice 120 min after induction, and 10 μM histamine perfusion reversed this enhancement. Paired-pulse facilitation (PPF) was significantly decreased after the LTP induction in HDC-KO mice compared with that in WT mice. 1 day after training, LTP in HDC-KO mice was decreased compared with WT mice, which implied involvement of activity-dependent LTP in associative learning and memory. And HPLC analysis showed that hippocampal glutamate content increased in HDC-KO mice 1d and 4d after training. The results indicated that LTP increase in HDC-KO mice, and presynaptic gluatamate release may be also involved during the process. The changes in synaptic plasiticity in the hippocampus may contribute to the improvement in learning and memory. Summary
1. Contextual fear memory increased in HDC-KO mice from 2h to 14d after training, and long-term histamine deficiency may upregulate hippocampal acquisition and consolidation of contextual fear. While these influences may be not specific to the hippocampus, amygdala may also be involved in the process.
2. The electrophysiological recording showed that there was no difference in input-out curve between the two genotypes, which indicated the basal synaptic transmission do not change in HDC-KO mice. And long-term histamine deficiency may increase LTP in HDC-KO mice, while LTD did not change. Hippocampal glutamate content increase 1d and 4d after training, and PPF decrease after LTP induction indicated that presynaptic glutamate release may be involved in the enhancement of contexutal fear and LTP.
3. LTP in HDC-KO mice was significantly decreased compared with that in WT mice 1d after training. These results indicated that the synaptic efficiency increases 1d after contextual fear training, and this phenomenon may be closely related to activity-dependent LTP in associative learning and memory.
4. In the present study, we provide additional evidence that histamine is involved in acquisition and consolidation of contextual fear memory in a hippocampal -dependent manner. Fourthermore, we demonstrated that long-term histamine deficiency may contribute to improved contextual fear memory and spatial memory in HDC-KO mice. Compared with the effects of exogenous histamine on learning and memory, we elucidated the relationship between endogenous histamine deficiency and synaptic plasiticity, which provide a new aspect in this field.
组胺作为神经系统的递质或调质，在许多中枢活动中起着重要的调节作用，如神经内分泌调节、饮水摄食调节、体温调节、觉醒—睡眠、运动、攻击行为以及学习记忆等。学习记忆是脑的高级功能，在许多发病率较高的中枢神经系统疾病中，病人的学习记忆功能均受到不同程度的损害。因此，组胺与学习记忆的关系成为越来越多的研究者致力的热点问题。但随着研究的深入，人们发现组胺系统对学习记忆的影响十分复杂，对组胺以及组胺系统的相关药物在行为学方面的研究均出现不一致的结果。其中较为重要的原因是，组胺系统的药理学工具特异性相对较低，并没有选择性的、能够显著持久的抑制脑内组胺合成，及同时拮抗所有组胺受体的工具药。因此，越来越多的研究者采用HDC基因敲除(HDC-KO)小鼠来探讨组胺长期缺乏后对学习记忆的影响。研究表明，HDC-KO小鼠对物体的辨别记忆能力较其野生型(wild type，WT)小鼠下降，而在水迷宫和被动回避反应的学习记忆能力增强，并认为其与多巴胺的负性增强有关。但是这种假设需要在其它学习记忆模型中进一步证明，同时这些研究均停留在行为学水平，没有探讨其增强效应的深入机制。由于背景和空间学习记忆与海马结构的突触可塑性密切相关，在组胺的长期缺乏的情况下是否影响HDC-KO小鼠的海马的突触可塑性，而且在学习记忆的行为学任务中，这种突触可塑性是否发生改变，如何改变，至今仍不清楚。
因此为了进一步研究组胺长期缺乏对学习记忆的影响及其深入机制，本研究采用海马依赖的背景恐惧记忆模型，观察HDC-KO小鼠的学习记忆改变；同时用细胞外电生理记录HDC-KO小鼠突触可塑性的改变，探讨行为学改变的生理机制。
第一部分HDC基因敲除小鼠背景恐惧记忆的改变
近年来，恐惧条件反射模型(Pavlovian fear conditioning)逐渐成为研究学习记忆神经生物学机制的主要行为学模型，分为背景恐惧条件反射(cntextual fearconditioning)和线索恐惧条件反射(cued fear conditioning)。在这个模型中，小鼠需要在训练中将仪器背景刺激及声音刺激(conditioned stimulus)和足底电刺激(unconditioned stimulus)联系起来，产生对背景或声音的恐惧记忆，当小鼠再次暴露到相同背景或者在不同背景中的声音刺激时，小鼠会表现出呆滞反应(freezing)，其持续时间的长短是衡量恐惧记忆能力的标志。背景恐惧记忆而不是线索恐惧记忆依赖于海马。为了进一步研究组胺长期缺乏在海马依赖的学习记忆的重要作用，我们采用背景恐惧条件反射模型，观察HDC-KO小鼠的学习记忆是否发生改变。RT-PCR和高效液相结果显示HDC-KO小鼠不含有HDC基因，而且体内组胺含量极低。免疫印记发现HDC-KO小鼠海马细胞膜H2受体上调。行为学结果显示，给予电刺激后，HDC-KO小鼠的呆滞反应时间百分率从2h开始较WT小鼠升高，至训练后1d有显著性升高，并且一直持续到训练后14d。这些结果提示HDC-KO小鼠对背景恐惧记忆较WT小鼠显著增强，其时程的改变提示组胺长期缺乏可能参与海马的获得和巩固。我们进一步在训练前、训练后以及测试前脑室内注射组胺来确定背景恐惧记忆的增强，同时探讨组胺的缺乏将影响获得、巩固和再现中的哪个过程。结果发现，在训练前、训练后注射组胺明显降低HDC-KO小鼠呆滞反应的时间百分率，在测试前注射没有影响，证明组胺长期缺乏可能影响了海马的获得和巩固过程，对再现过程没有影响。对线索恐惧记忆的结果表明，HDC-KO小鼠在未受电击的环境中受到声音刺激时，其呆滞反应时间也延长，提示组胺长期缺乏导致的学习记忆增强对海马的依赖可能不是特异性的。
第二部分HDC基因敲除小鼠的突触可塑性改变
海马在学习记忆过程中突触可塑性的形成重要作用，海马的长时程增强(Long-term potentiation，LTP)是研究的最为广泛的活性依赖的突触可塑性的模型，被认为是学习记忆的神经基础。海马齿状回、CA3、CA1均有习得性长时程增强的突触效应，其中以Schaffer侧支与CA1形成的通路与空间背景学习记忆关系最为密切。在第一部分中，我们已经发现组胺的长期缺乏增强HDC-KO小鼠的背景学习记忆，并影响获得和巩固过程。在本部分实验中，主要研究行为学改变的突触可塑性机制。细胞外电生理结果显示，HDC-KO小鼠的基本输入输出曲线(input-output curve)较WT小鼠没有明显改变，即CA1区的基本突触传递并没有因为敲除HDC基因而改变；在TBS刺激后HDC-KO小鼠的群峰电位增强的幅度明显高于WT小鼠，即HDC-KO小鼠的LTP较WT小鼠显著增强，并可以持续2h直到记录结束；10μM组胺灌流小鼠海马脑片，给予TBS刺激诱导LTP后，其幅度明显下降，说明HDC-KO小鼠LTP的增强是由组胺的长期缺乏特异性引起的；HDC-KO小鼠的双脉冲易化在LTP诱导前后有明显差异，特别是诱导后较WT小鼠显著下降，提示在LTP诱导后，HDC-KO小鼠的突触前谷氨酸释放增加，参与了LTP的增强效应；而在训练后1d时，两种基因型小鼠的LTP较正常时均明显下降，但WT小鼠的LTP幅度反而明显高于HDC-KO小鼠的LTP，提示HDC-KO小鼠的背景恐惧记忆明显增强时，突触传递已经维持在较高的水平，LTP出现饱和现象，进一步证明其行为学的改变，以及LTP与联合性学习记忆的相关性。
总结
1．内源性组胺长期缺乏导致背景恐惧记忆增强，这种增强作用从训练后2h开始，一直持续到14d。组胺脑室内注射提示，组胺长期缺乏对海马的获得和巩固过程有明显影响。HDC-KO小鼠对声音的恐惧记忆亦增强，提示组胺长期缺乏对背景恐惧记忆的影响并不是特异性的，其不仅对海马的功能有影响，也可能影响杏仁核的功能。
2．两种基因型小鼠海马脑片的电生理记录显示，虽然HDC-KO小鼠的输入输出曲线左移，但与WT对照小鼠比较没有显著性差异，提示HDC-KO小鼠的基本电生理特性没有发生明显改变；内源性组胺长期缺乏导致HDC-KO小鼠海马脑片CA1区LTP增强，而LTD没有发生明显变化；LTP诱导前和诱导后的PPF下降，以及生化结果发现行为学训练后1d和4d海马内谷氨酸含量增加，提示突触前谷氨酸释放增加可能参与背景恐惧记忆和LTP的增强效应；
3．HDC-KO小鼠训练后1d海马脑片电生理记录显示，LTP幅度较WT小鼠明显降低，提示训练后1d背景恐惧增强时其突触效能已经明显增强，LTP与联合性学习记忆的密切相关。
4．本研究进一步阐明HDC-KO小鼠对海马依赖的背景恐惧记忆影响，并首次揭示了本实验和以往实验中学习记忆改变的机制，即内源性组胺长期缺乏可能导致海马CA1区突触传递的增强，对比以往局限于外源性组胺的研究，我们的结果从相反的角度深化了组胺与突触可塑性关系的认识，为今后组胺在学习记忆方面的基础和临床研究提供了新的思路。
Histamine is one of the most widely distributed inflammatory substances in the body. Compared with other aminergic systems, the histaminergic system in the CNS gained general acceptance only in 1984, after the immunohistochemical demonstration that the tuberomamillary (TM) nucleus was the sole seat of histaminergic neurons and the origin of the widely distributed histaminergic projections. It is now thought that their efferent fibers project to almost the entire brain, including the hypothalamus, septum, thalamus, cortex, amygdala, and hippocampus. Histamine is synthesised in brain from L-histidine by the enzyme histidine decarboxylase (HDC), and up to now HDC is the only enzyme catalyzed the process. Four histamine receptors have been cloned (H1-H4), and the H1, H2 and H3 histamine receptors are all expressed in distinctive patterns in the brain. The H1 receptor is a 486-491 amino acid protein encoded by an intronless gene, and is coupled to the Gq/11 protein and phospholipase C. The H2 receptor is coupled to Gs and protein kinase A and the protein consists of 358-359 amino acids. The H3 autoreceptor is coupled to Gi/Go, displays a significant constitutive activity, and controls histamine release and synthesis. The H3 receptor regulates the release of several transmitters in brain areas, such as the substantia nigra, amygdala and cerebral cortex.
Histamine controls a variety of neurobiological functions and behavioral responses including sleep-wake cycle, water consumption, food, motor activity, and nociception. Histamine is also involved in learning and memory, and many researchers have contributed a lot in this field. However, these studies yielded to contradictory results. For instance, histamine improved and impaired active avoidance conditioning. The HDC-blocker α-iluoromethylhistidine (α-FMH) also has those effects in a radial-maze task. Furthermore, H_1 receptor antagonism has different influence on spatial memory performance and some emotional tasks. There were also discrepancies found with H_2 receptor antagonists and agonists and H3 receptor. The mechanisms underlying these differences seem to be very complex, which may be in part due to the methods used and the approaches selected in the experiments. Most histaminergic agents, and lesions of the TM and hippocampus, not only influence the histaminergic system but also affect non-histaminergic systems in the brain. So, recently histidine decarboxylase knockout (HDC-KO) mice have been developed to study the role of the histaminergic system in learning and other behaviors more specifically and to explain these discrepancies. Previous research showed that HDC-KO mice had improved water maze performance during both hidden and cued platform tasks, but exhibit deficient object discrimination based on temporal relationships. It is proposed that disruption of brain histamine synthesis may actually have bidirectional effects on learning and memory related to the reinforcement contingencies inherent in the task. However, this hypothesis needs further confirmation. Furthermore, these studies have not explained the mechanisms of the enhancement of learning and memory in the behavioral tasks. Contextual and spatial learning and memory is closely related to the synaptic plasiticity, and it is still unclear whether long-term histamine deficiency influences the synaptic plasiticity during the behavioral performance in HDC-KO mice.
In the present study, we investigated the change of learning and memory in hippocampal-dependent contextual fear conditioning, and the synaptic plasiticity in hippocampal CA1 region using electrophysiological recording to explain the mechanisms of behavioral performance in HDC-KO mice.
Part I Contextual fear conditioning in HDC-KO mice
Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. It can be divided into contextual fear conditioning and cued fear conditioning according to the conditioned sitmulus. Contextual but not cued fear memory is dependent on the hippocampus. In this paradigm, mice were given the opportunity to associate both a tone (cue) and the apparatus (context) with footshock in a single training trial. Memory was assessed by scoring the percent time mice spent immobile (freezing, a fear reaction) upon reexposure either to the context or the cue in a distinct context. In this part of investigation, we used contextual fear conditioning to examine learning and memory ability in HDC-KO mice. The data showed that mice lacking histamine exhibited improved contextual fear memory, and this improvement was maintained for a long period from 2h to 14d. The intracerebroventricular injection of histamine before and immediately after training reversed the improvement, while the injection before testing had on effects. HDC-KO mice also showed enhancement of cued fear compared with the wildtype (WT) mice. The results indicated that contextual fear memory increased in HDC-KO mice from 2h to 14d after training, and long-term histamine deficiency may upregulate hippocampal acquisition and consolidation of contextual fear. While these influences may be not specific to the hippocampus, amygdala may also be involved in the process. Part II synaptic plasiticity in the hippocampal CA1 region in
HDC-KO mice
Hippocampus plays an important role in synaptic plasiticity. Physiologial activity-dependent long-term changes in synaptic transmission, as long-term potentiation (LTP) are thought to be the substrate of learning and memory. Contextual and spatial learning and memory are closely related to the LTP in the synapse from the Schaffer collateral pathway to CA1 cells. We found that long-term histamine deficiency increased the acquisition and consolidation of contextual fear in HDC-KO mice. In this part, we investigated the synaptic plasiticity in hippocampal CA1 region to explain the behavioral performance in HDC-KO mice. The data showed that there was no difference in input-out curve and LTD between the two genotypes. While under normal conditions, LTP was stronger in HDC-KO mice than that in WT mice 120 min after induction, and 10 μM histamine perfusion reversed this enhancement. Paired-pulse facilitation (PPF) was significantly decreased after the LTP induction in HDC-KO mice compared with that in WT mice. 1 day after training, LTP in HDC-KO mice was decreased compared with WT mice, which implied involvement of activity-dependent LTP in associative learning and memory. And HPLC analysis showed that hippocampal glutamate content increased in HDC-KO mice 1d and 4d after training. The results indicated that LTP increase in HDC-KO mice, and presynaptic gluatamate release may be also involved during the process. The changes in synaptic plasiticity in the hippocampus may contribute to the improvement in learning and memory. Summary
1. Contextual fear memory increased in HDC-KO mice from 2h to 14d after training, and long-term histamine deficiency may upregulate hippocampal acquisition and consolidation of contextual fear. While these influences may be not specific to the hippocampus, amygdala may also be involved in the process.
2. The electrophysiological recording showed that there was no difference in input-out curve between the two genotypes, which indicated the basal synaptic transmission do not change in HDC-KO mice. And long-term histamine deficiency may increase LTP in HDC-KO mice, while LTD did not change. Hippocampal glutamate content increase 1d and 4d after training, and PPF decrease after LTP induction indicated that presynaptic glutamate release may be involved in the enhancement of contexutal fear and LTP.
3. LTP in HDC-KO mice was significantly decreased compared with that in WT mice 1d after training. These results indicated that the synaptic efficiency increases 1d after contextual fear training, and this phenomenon may be closely related to activity-dependent LTP in associative learning and memory.
4. In the present study, we provide additional evidence that histamine is involved in acquisition and consolidation of contextual fear memory in a hippocampal -dependent manner. Fourthermore, we demonstrated that long-term histamine deficiency may contribute to improved contextual fear memory and spatial memory in HDC-KO mice. Compared with the effects of exogenous histamine on learning and memory, we elucidated the relationship between endogenous histamine deficiency and synaptic plasiticity, which provide a new aspect in this field.
引文
1. Garbarg, M., et al., Histaminergic pathway in rat brain evidenced by lesions of the medial forebrain bundle. Science, 1974.186(4166): p. 833-5.
2. Panula, P., H.Y. Yang, and E. Costa, Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A, 1984. 81(8): p. 2572-6.
3. Watanabe, T., et al., Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res, 1984. 295(1): p. 13-25.
4. Schwartz, J.C., et al., Histaminergic transmission in the mammalian brain. Physiol Rev, 1991. 71(1): p. 1-51.
5. Bouthenet, M.L., et al., A detailed mapping of histamine H1-receptors in guinea-pig central nervous system established by autoradiography with [125I]iodobolpyramine. Neuroscience, 1988. 26(2): p. 553-600.
6. Martinez-Mir, M.I., et al., Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res, 1990. 526(2): p. 322-7.
7. Morisset, S., et al., High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature, 2000. 408(6814): p. 860-4.
8. Arrang, J.M., et al., Molecular and functional diversity of histamine receptor subtypes. Ann N Y Acad Sci, 1995.757: p. 314-23.
9. Zhang, L., et al., Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats. Eur J Pharmacol, 2003.482(1-3): p. 169-75.
10. Jin, C.L., et al., Lesion of the tuberomammiUary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res, 2007. 73(3): p. 250-8.
11. Huang, Y.W., et al., Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluated by radial maze in Sprague-Dawley rats. Behav Brain Res, 2004.151(1-2): p. 287-93.
12. Chen, Z., et al., Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats. Brain Res, 1999. 839(1): p. 186-9.
13. Adachi, N., R. Oishi, and K. Saeki, Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem, 1991.57(1): p. 61-6.
14. Kamei, C, Y. Okumura, and K. Tasaka, Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology (Berl), 1993. 111(3): p. 376-82.
15. Alvarez, E.O. and A.M. Banzan, Hippocampus and learning: possible role of histamine receptors. Medicina (B Aires), 1996. 56(2): p. 155-60.
16. Sakai, N., et al., Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels. Life Sci, 1998. 62(11): p. 989-94.
17. Chen, Z., Y. Sugimoto, and C. Kamei, Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav, 1999. 64(3): p. 513-8.
18. Hasenohrl, R.U., K. Weth, and J.P. Huston, Intraventricular infusion of the histamine H(l) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res, 1999.128(4): p. 435-40.
19. Taga, C, et al., Effects of vasopressin on histamine H(1) receptor antagonist-induced spatial memory deficits in rats. Eur J Pharmacol, 2001. 423(2-3): p. 167-70.
20. Yanai, K., et al., Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 1998. 87(2): p. 479-87.
21. Yanai, K., et al., Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci, 1998. 62(17-18): p. 1607-10.
22. Flood, J.F., K. Uezu, and J.E. Morley, Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing. Psychopharmacology (Berl), 1998.140(3): p. 279-84.
23. Onodera, K., et al., Neuropharmacology of the histaminergic neuron system in the brain and its relationship with behavioral disorders. Prog Neurobiol, 1994. 42(6): p. 685-702.
24. Blandina, P., et al., Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br J Pharmacol, 1996. 119(8): p. 1656-64.
25. Rubio, S., et al., Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res, 2002.129(1-2): p. 77-82.
26. Watanabe, T., et al., Pharmacology of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol Sci, 1990. 11(9): p. 363-7.
27. Onodera, K.., A. Yamatodani, and T. Watanabe, Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats. Methods Find Exp Clin Pharmacol, 1992. 14(2): p. 97-105.
28. Hill, S.J., et al., International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev, 1997.49(3): p. 253-78.
29. Haas, H. and P. Panula, The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci, 2003.4(2): p. 121-30.
30. Ohtsu, H., et al., Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett, 2001.502(1-2): p. 53-6.
31. Kubota, Y., et al., Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice. J Neurochem, 2002. 83(4): p. 837-45.
32. Iwabuchi, K., et al., Methamphetamine and brain histamine: a study using histamine-related gene knockout mice. Ann N Y Acad Sci, 2004. 1025: p. 129-34.
33. Dere, E., et al., Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci, 2004. 20(4): p. 1051-8.
34. Bliss, T.V. and G.L. Collingridge, A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 1993.361(6407): p. 31-9.
35. Nakazawa, K., et al., NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci, 2004. 5(5): p. 361-72.
36. Bliss, T.V. and A.R. Gardner-Medwin, Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path. J Physiol, 1973. 232(2): p. 357-74.
37. Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus. Science, 1993.261(5117): p. 104-6.
38. Vorobjev, V.S., et al., Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron, 1993.11(5): p. 837-44.
39. Williams, K., Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 1994. 46(3): p. 531-41.
40. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CAl of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
41. Payne, G.W. and R.S. Neuman, Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses. Br J Pharmacol, 1997. 121(2): p. 199-204.
42. Selbach, O., R.E. Brown, and H.L. Haas, Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology, 1997. 36(11-12): p. 1539-48.
43. Brown, R.E. and H.L. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus. J Physiol, 1999.515 (Pt 3): p. 777-86.
44. Kim, J.J. and M.S. Fanselow, Modality-specific retrograde amnesia of fear. Science, 1992. 256(5057): p. 675-7.
45. Phillips, R.G. and J.E. LeDoux, Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci, 1992. 106(2): p. 274-85.
1. Zhang, L., et al., Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats. Eur J Pharmacol, 2003.482(1-3): p. 169-75.
2. Jin, C.L., et al., Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res, 2007. 73(3): p. 250-8.
3. Huang, Y.W., et al., Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluated by radial maze in Sprague-Dawley rats. Behav Brain Res, 2004.151(1-2): p. 287-93.
4. Chen, Z., et al., Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats. Brain Res, 1999. 839(1): p. 186-9.
5. Adachi, N., R. Oishi, and K. Saeki, Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem, 1991.57(1): p. 61-6.
6. Flood, J.F., K. Uezu, and J.E. Morley, Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing. Psychopharmacology (Berl), 1998.140(3): p. 279-84.
7. Sakai, N., et al., Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels. Life Sci, 1998. 62(11): p. 989-94.
8. Yanai, K., et al., Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 1998.87(2): p. 479-87.
9. Yanai, K., et al., Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci, 1998. 62(17-18): p. 1607-10.
10. Chen, Z., Y. Sugimoto, and C. Kamei, Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav, 1999. 64(3): p. 513-8.
11. Hasenohrl, R.U., KL Weth, and J.P. Huston, Intraventricular infusion of the histamine H(1) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res, 1999.128(4): p. 435-40.
12. Taga, C, et al., Effects of vasopressin on histamine H(l) receptor antagonist-induced spatial memory deficits in rats. Eur J Pharmacol, 2001. 423(2-3): p. 167-70.
13. Rubio, S., et al., Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res, 2002.129(1-2): p. 77-82.
14. Watanabe, T., et al., Pharmacology of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol Sci, 1990.11(9): p. 363-7.
15. Onodera, K., A. Yamatodani, and T. Watanabe, Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats. Methods Find Exp Clin Pharmacol, 1992.14(2): p. 97-105.
16. Hill, S J., et al., International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev, 1997.49(3): p. 253-78.
17. Haas, H. and P. Panula, The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci, 2003. 4(2): p. 121-30.
18. Kim, J J. and M.S. Fanselow, Modality-specific retrograde amnesia of fear. Science, 1992. 256(5057): p. 675-7.
19. Phillips, R.G. and J.E. LeDoux, Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci, 1992. 106(2): p. 274-85.
20. Toyoda, M., H. Saito, and N. Matsuki, Nitric oxide but not carbon monoxide is involved in spatial learning of mice. Jpn J Pharmacol, 1996.71(3): p. 205-11.
21. Glowinski, J. and L.L. Iversen, Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem, 1966.13(8): p. 655-69.
22. Zhu, L.J., et al., Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. Neurosci Lett, 2004.356(1): p. 53-6.
23. Ohtsu, H., et al., Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett, 2001.502(1-2): p. 53-6.
24. Parmentier, R., et al., Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci, 2002. 22(17): p. 7695-711.
25. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CA1 of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
26. Dere, E., et al., Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci, 2004.20(4): p. 1051-8.
27. Acevedo, S.F., et al., Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice. Brain Res, 2006.1071(1): p. 113-23.
28. Blanchard, R J. and D.C. Blanchard, Crouching as an index of fear. J Comp Physiol Psychol, 1969.67(3): p. 370-5.
29. LeDoux, J.E., Brain mechanisms of emotion and emotional learning. Curr Opin Neurobiol, 1992.2(2): p. 191-7.
30. Anagnostaras, S.G., G.D. Gale, and M.S. Fanselow, Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus, 2001.11(1): p. 8-17.
31. Jorgensen, E.A., et al., Increased susceptibility to diet-induced obesity in histamine-deficient mice. Neuroendocrinology, 2006.83(5-6): p. 289-94.
32. Morris, R.G., et al., Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos Trans R Soc Lond B Biol Sci, 2003.358(1432): p. 773-86.
33. Hirsh, R., The hippocampus and contextual retrieval of information from memory: a theory. Behav Biol, 1974.12(4): p. 421-44.
34. McClelland, J.L., B.L. McNaughton, and R.C. O'Reilly, Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev, 1995.102(3): p. 419-57.
35. Squire, L.R., R.E. Clark, and B.J. Knowlton, Retrograde amnesia. Hippocampus, 2001.11(1): p. 50-5.
36. Jensen, R.A., et al., Benzodiazepines alter acquisition and retention of an inhibitory avoidance response in mice. Psychopharmacology (Berl), 1979. 64(1): p. 125-6.
37. Martinez, J.L., Jr., et al., ACTH4-9 analog (ORG 2766) facilitates acquisition of an inhibitory avoidance response in rats. Pharmacol Biochem Behav, 1979. 10(1): p. 145-7.
38. Passani, M.B., et al., Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala. Eur J Neurosci, 2001.14(9): p. 1522-32.
39. Cangioli, I., et al., Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release. Eur J Neurosci, 2002.16(3): p. 521-8.
40. Baldi, E., et al., The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat. Neuropharmacology, 2005.48(2): p. 246-51.
41. de Almeida, M.A. and I. Izquierdo, Memory facilitation by histamine. Arch Int Pharmacodyn Ther, 1986.283(2): p. 193-8.
42. de Almeida, M.A. and I. Izquierdo, Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch Int Pharmacodyn Ther, 1988.291: p. 202-7.
43. Kamei, C. and K. Tasaka, Effect of histamine on memory retrieval in old rats. Biol Pharm Bull, 1993.16(2): p. 128-32.
44. Alvarez, E.O. and A.M. Banzan, Effects of localized histamine microinjections into the hippocampal formation on the retrieval of a one-way active avoidance response in rats. J Neural Transm Gen Sect, 1995.101(1-3): p. 201-11.
45. Eidi, M., et al., Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2003.465(1-2): p. 91-6.
46. Huston, J.P., U. Wagner, and R.U. Hasenohrl, The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role. Behav Brain Res, 1997. 83(1-2): p. 97-105.
47. Zarrindast, M.R., et al., Effects of histamine and opioid systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2002.452(2): p. 193-7.
1. Bliss, T.V. and G.L. Collingridge, A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 1993.361(6407): p. 31-9.
2. Nakazawa, K., et al., NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci, 2004.5(5): p. 361-72.
3. Bliss, T.V. and A.R. Gardner-Medwin, Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path. J Physiol, 1973.232(2): p. 357-74.
4. Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus. Science, 1993.261(5117): p. 104-6.
5. Vorobjev, V.S., et al., Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron, 1993.11(5): p. 837-44.
6. Williams, K., Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 1994. 46(3): p. 531-41.
7. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CAl of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
8. Payne, G.W. and R.S. Neuman, Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses. Br J Pharmacol, 1997. 121(2): p. 199-204.
9. Selbach, O., R.E. Brown, and H.L. Haas, Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology, 1997. 36(11-12): p. 1539-48.
10. Brown, R.E. and H.L. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyms. J Physiol, 1999. 515 (Pt 3): p. 777-86.
11. Debanne, D., et al., Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release. J Physiol, 1996. 491 (Pt 1): p. 163-76.
12. Foster, T.C. and B.L. McNaughton, Long-term enhancement of CA1 synaptic transmission is due to increased quantal size, not quantal content. Hippocampus, 1991.1(1): p. 79-91.
13. Hess, G., U. Kuhnt, and L.L. Voronin, Quantal analysis of paired-pulse facilitation in guinea pig hippocampal slices. Neurosci Lett, 1987. 77(2): p. 187-92.
14. Del Castillo, J. and B. Katz, Statistical factors involved in neuromuscular facilitation and depression. J Physiol, 1954. 124(3): p. 574-85.
15. Zhao, M.G., et al., Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron, 2005. 47(6): p. 859-72.
16. Lynch, G.S., T. Dunwiddie, and V. Gribkoff, Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature, 1977. 266(5604): p. 737-9.
17. Linden, D.J. and J.A. Connor, Long-term synaptic depression. Annu Rev Neurosci, 1995. 18: p. 319-57.
18. Garcia, M., et al., Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience, 1997. 80(1): p. 241-9.
19. Lynch, M.A., Long-term potentiation and memory. Physiol Rev, 2004. 84(1): p. 87-136.
20. Dere, E., et al., Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover. Learn Mem, 2003.10(6): p. 510-9.
21. Liu, L., et al., Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science, 2004.304(5673): p. 1021-4.
22. Frey, U., et al., The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CAl region in vitro. Neurosci Lett, 1991.129(1): p. 111-4.
23. Huang, Y.Y. and E.R. Kandel, D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CAl region of the hippocampus. Proc Natl Acad Sci U S A, 1995. 92(7): p. 2446-50.
24. Lemon, N. and D. Manahan-Vaughan, Dopamine D1/D5 receptors gate the acquisition of novel information through hippocampal long-term potentiation and long-term depression. J Neurosci, 2006. 26(29): p. 7723-9.
25. Gao, C, X. Sun, and M.E. Wolf, Activation of Dl dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons. J Neurochem, 2006.
26. Doreulee, N., et al., Histamine H(3) receptors depress synaptic transmission in the corticostriatal pathway. Neuropharmacology, 2001.40(1): p. 106-13.
27. Parnas, H., I. Parnas, and L.A. Segel, On the contribution of mathematical models to the understanding of neurotransmitter release. Int Rev Neurobiol, 1990.32: p. 1-50.
28. Li, Z., et al., Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CAl area in vivo. Hippocampus, 2005.15(6): p. 815-24.
29. Barnes, C, et al., LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J. Neurosci., 1994.14(10): p. 5793-5806.
30. McNaughton, B.L., et al., Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information. J Neurosci, 1986.6(2): p. 563-71.
31. Moser, E.I., et al., Impaired spatial learning after saturation of long-term potentiation. Science, 1998.281(5385): p. 2038-42.
32. Gruart, A., M.D. Munoz, and J.M. Delgado-Garcia, Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci, 2006.26(4): p. 1077-87.
1. Garbarg, M., et al., Histaminergic pathway in rat brain evidenced by lesions of the medial forebrain bundle. Science, 1974.186(4166): p. 833-5.
2. Panula, P., H.Y. Yang, and E. Costa, Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A, 1984. 81(8): p. 2572-6.
3. Watanabe, T., et al., Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res, 1984.295(1): p. 13-25.
4. Garbarg, M., et al., Dual localization of histamine in an ascending neuronal pathway and in non-neuronal cells evidenced by lesions in the lateral hypothalamic area. Brain Res, 1976.106(2): p. 333-48.
5. Dropp, J.J., Mast cells in the human brain. Acta Anat (Basel), 1979. 105(4): p. 505-13.
6. Theoharides, T.C., Mast cells: the immune gate to the brain. Life Sci, 1990. 46(9): p. 607-17.
7. Hu, W., et al., Effect of cerebral ischemia on brain mast cells in rats. Brain Res, 2004.1019(1-2): p. 275-80.
8. Hough, L.B., Cellular localization and possible functions for brain histamine: recent progress. Prog Neurobiol, 1988.30(6): p. 469-505.
9. Prell, G.D. and J.P. Green, Histamine as a neuroregulator. Annu Rev Neurosci, 1986.9: p. 209-54.
10. Lin, J.S., et al., Immunohistochemical evidence for the presence of type B monoamine oxidase in histamine-containing neurons in the posterior hypothalamus of cats. Neurosci Lett, 1991.128(1): p. 61-5.
11. Schwartz, J.C., et al., Histaminergic transmission in the mammalian brain. Physiol Rev, 1991.71(1): p. 1-51.
12. Arrang, J.M., M. Garbarg, and J.C. Schwartz, Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature, 1983. 302(5911): p. 832-7.
13. Itoh, Y., et al., Characterization of histamine release from the rat hypothalamus as measured by in vivo microdialysis. J Neurochem, 1991.56(3): p. 769-74.
14. Prast, H., et al., In vivo modulation of histamine release by autoreceptors and muscarinic acetylcholine receptors in the rat anterior hypothalamus. Naunyn Schmiedebergs Arch Pharmacol, 1994.350(6): p. 599-604.
15. Panula, P., et al., Histamine-immunoreactive nerve fibers in the rat brain. Neuroscience, 1989.28(3): p. 585-610.
16. Kaslin, J. and P. Panula, Comparative anatomy of the histaminergic and other aminergic systems in zebrafish (Danio rerio). J Comp Neurol, 2001. 440(4): p. 342-77.
17. Vincent, S.R., et al., Hypothalamic gamma-aminobutyric acid neurons project to the neocortex. Science, 1983.220(4603): p. 1309-11.
18. Takeda, N., et al., Immunohistochemical evidence for the coexistence of histidine decarboxylase-like and glutamate decarboxylase-like immunoreactivities in nerve cells of the magnocellular nucleus of the posterior hypothalamus of rats. Proc Natl Acad Sci U S A, 1984. 81(23): p. 7647-50.
19. Senba, E., P.E. Daddona, and J.I. Nagy, Adenosine deaminase-containing neurons in the olfactory system of the rat during development. Brain Res Bull, 1987.18(5): p. 635-48.
20. Ericson, H., C. Kohler, and A. Blomqvist, GABA-like immunoreactivity in the tuberomammillary nucleus: an electron microscopic study in the rat. J Comp Neurol, 1991.305(3): p. 462-9.
21. Airaksinen, M.S., et al., Multiple neurotransmitters in the tuberomammillary nucleus: comparison of rat, mouse, and guinea pig. J Comp Neurol, 1992.323(1): p. 103-16.
22. Staines, W.A., et al., Neuronal colocalization of adenosine deaminase, monoamine oxidase, galanin and 5-hydroxytryptophan uptake in the tuberomammillary nucleus of the rat. Brain Res Bull, 1986.17(3): p. 351-65.
23. Nguyen, T., et al., Discovery of a novel member of the histamine receptor family. Mol Pharmacol, 2001.59(3): p. 427-33.
24. Bouthenet, M.L., et al., A detailed mapping of histamine H1-receptors in guinea-pig central nervous system established by autoradiography with [125I]iodobolpyramine. Neuroscience, 1988.26(2): p. 553-600.
25. Martinez-Mir, M.I., et al., Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res, 1990. 526(2): p. 322-7.
26. Leurs, R., et al., H3 receptor gene is cloned at last. Trends Pharmacol Sci, 2000. 21(1): p. 11-2.
27. Yamashita, M., et al., Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc Natl Acad Sci U S A, 1991. 88(24): p. 11515-9.
28. Leurs, R., et al., Guinea pig histamine H1 receptor. II. Stable expression in Chinese hamster ovary cells reveals the interaction with three major signal transduction pathways. J Neurochem, 1994. 62(2): p. 519-27.
29. Black, J.W., et al., Definition and antagonism of histamine H 2 -receptors. Nature, 1972.236(5347): p. 385-90.
30. Traiffort, E., et al., The guinea pig histamine H2 receptor: gene cloning, tissue expression and chromosomal localization of its human counterpart. Biochem Biophys Res Commun, 1995. 211(2): p. 570-7.
31. Coge, F., et al., Genomic organization and characterization of splice variants of the human histamine H3 receptor. Biochem J, 2001. 355(Pt 2): p. 279-88.
32. Drutel, G., et al., Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol Pharmacol, 2001.59(1): p. 1-8.
33. Lovenberg, T.W., et al., Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol, 1999.55(6): p. 1101-7.
34. Morisset, S., et al., High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature, 2000.408(6814): p. 860-4.
35. Arrang, J.M., et al., Molecular and functional diversity of histamine receptor subtypes. Ann N Y Acad Sci, 1995.757: p. 314-23.
36. Richelson, E., Histamine H1 receptor-mediated guanosine 3',5'-monophosphate formation by cultured mouse neuroblastoma cells. Science, 1978. 201(4350): p. 69-71.
37. Baudry, M., M.P. Martres, and J.C. Schwartz, H1 and H2 receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices. Nature, 1975.253(5490): p. 362-4.
38. Daum, P.R., S.J. Hill, and J.M. Young, Histamine H1-agonist potentiation of adenosine-stimulated cyclic AMP accumulation in slices of guinea-pig cerebral cortex: comparison of response and binding parameters. Br J Pharmacol, 1982. 77(2): p. 347-57.
39. Chang, R.S., V.T. Tran, and S.H. Snyder, Heterogeneity of histamine H1-receptors: species variations in [3H]mepyramine binding of brain membranes. J Neurochem, 1979.32(6): p. 1653-63.
40. Palacios, J.M., J.K. Wamsley, and M.J. Kuhar, The distribution of histamine Hl-receptors in the rat brain: an autoradiographic study. Neuroscience, 1981. 6(1): p. 15-37.
41. Selbach, O., R.E. Brown, and H.L. Haas, Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology, 1997. 36(11-12): p. 1539-48.
42. Brown, R.E., D.R. Stevens, and H.L. Haas, The physiology of brain histamine. Prog Neurobiol, 2001.63(6): p. 637-72.
43. Yanovsky, Y. and H.L. Haas, Histamine increases the bursting activity of pyramidal cells in the CA3 region of mouse hippocampus. Neurosci Lett, 1998. 240(2): p. 110-2.
44. Traiffort, E., et al., Pharmacological characterization and autoradiographic localization of histamine H2 receptors in human brain identified with [125I]iodoaminopotentidine. J Neurochem, 1992.59(1): p. 290-9.
45. Vizuete, M.L., et al., Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain. Neuroscience, 1997. 80(2): p. 321-43.
46. Brown, R.E. and K.G. Reymann, Histamine H3 receptor-mediated depression of synaptic transmission in the dentate gyrus of the rat in vitro. J Physiol, 1996.496 (Pt 1): p. 175-84.
47. Garcia, M., et al., Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience, 1997.80(1): p. 241-9.
48. Schlicker, E., et al., Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors. Naunyn Schmiedebergs Arch Pharmacol, 1989. 340(6): p. 633-8.
49. Schlicker, E., et al., Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. J Neural Transm Gen Sect, 1993. 93(1): p. 1-10.
50. Arrang, J.M., G. Drutel, and J.C. Schwartz, Characterization of histamine H3 receptors regulating acetylcholine release in rat entorhinal cortex. Br J Pharmacol, 1995.114(7): p. 1518-22.
51. Schlicker, E., R. Betz, and M. Gothert, Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol, 1988.337(5): p. 588-90.
52. Hill, SJ., et al., International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev, 1997. 49(3): p. 253-78.
53. Kamei, C, Y. Okumura, and K. Tasaka, Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology (Berl), 1993. 111(3): p. 376-82.
54. Alvarez, E.O. and A.M. Banzan, Hippocampus and learning: possible role of histamine receptors. Medicina (B Aires), 1996.56(2): p. 155-60.
55. Sakai, N., et al., Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino add levels. Life Sci, 1998. 62(11): p. 989-94.
56. Chen, Z., Y. Sugimoto, and C. Kamei, Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav, 1999. 64(3): p. 513-8.
57. Hasenohrl, R.U., K. Weth, and J.P. Huston, Intraventricular infusion of the histamine H(l) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res, 1999.128(4): p. 435-40.
58. Taga, C., et al., Effects of vasopressin on histamine H(l) receptor antagonist-induced spatial memory deficits in rats. Eur J Pharmacol, 2001. 423(2-3): p. 167-70.
59. Yanai, K., et al., Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 1998.87(2): p. 479-87.
60. Yanai, K., et al., Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci, 1998. 62(17-18): p. 1607-10.
61. Flood, J.F., K. Uezu, and J.E. Morley, Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing. Psychopharmacology (Berl), 1998.140(3): p. 279-84.
62. Onodera, K., et al., Neuropharmacology of the histaminergic neuron system in the brain and its relationship with behavioral disorders. Prog Neurobiol, 1994. 42(6): p. 685-702.
63. Blandina, P., et al., Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br J Pharmacol, 1996. 119(8): p. 1656-64.
64. Rubio, S., et al., Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res, 2002.129(1-2): p. 77-82.
65. de Almeida, M.A. and I. Izquierdo, Memory facilitation by histamine. Arch Int Pharmacodyn Ther, 1986.283(2): p. 193-8.
66. de Almeida, M.A. and I. Izquierdo, Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch Int Pharmacodyn Ther, 1988. 291: p. 202-7.
67. Kamei, C. and K. Tasaka, Effect of histamine on memory retrieval in old rats. Biol Pharm Bull, 1993.16(2): p. 128-32.
68. Alvarez, E.O. and A.M. Banzan, Effects of localized histamine microinjections into the hippocampal formation on the retrieval of a one-way active avoidance response in rats. J Neural Transm Gen Sect, 1995.101(1-3): p. 201-11.
69. Eidi, M., et al., Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2003. 465(1-2): p. 91-6.
70. Huston, J.P., U. Wagner, and R.U. Hasenohrl, The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role. Behav Brain Res, 1997.83(1-2): p. 97-105.
71. Zarrindast, M.R., et al., Effects of histamine and opioid systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2002. 452(2): p. 193-7.
72. Watanabe, T., et al., Pharmacology of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol Sci, 1990. 11(9): p. 363-7.
73. Onodera, K., A. Yamatodani, and T. Watanabe, Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats. Methods Find Exp Clin Pharmacol, 1992.14(2): p. 97-105.
74. Haas, H. and P. Panula, The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci, 2003.4(2): p. 121-30.
75. Dere, E., et al., Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci, 2004.20(4): p. 1051-8.
76. Acevedo, S.F., et al., Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice. Brain Res, 2006. 1071(1): p. 113-23.
77. Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus. Science, 1993.261(5117): p. 104-6.
78. Vorobjev, V.S., et al., Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron, 1993.11(5): p. 837-44.
79. Williams, K., Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 1994. 46(3): p. 531-41.
80. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CA1 of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
81. Payne, G.W. and R.S. Neuman, Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses. Br J Pharmacol, 1997. 121(2): p. 199-204.
82. Brown, R.E. and H.L. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus. J Physiol, 1999.515 (Pt 3): p. 777-86.
83. Lin, J.S., et al., A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. Brain Res, 1989.479(2): p. 225-40.
84. Parmentier, R., et al., Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci, 2002. 22(17): p. 7695-711.
85. Mochizuki, T., et al., In vivo release of neuronal histamine in the hypothalamus of rats measured by microdialysis. Naunyn Schmiedebergs Arch Pharmacol, 1991.343(2): p. 190-5.
86. Cecchi, M., et al., Cortical acetylcholine release elicited by stimulation of histamine H1 receptors in the nucleus basalis magnocellularis: a dual-probe microdialysis study in the freely moving rat. Eur J Neurosci, 2001. 13(1): p. 68-78.
87. Brown, R.E., et al., Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci, 2002.22(20): p. 8850-9.
88. Cangioli, I., et al., Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release. Eur J Neurosci, 2002.16(3): p. 521-8.
89. Strecker, R.E., et al., Extracellular histamine levels in the feline preoptic/anterior hypothalamic area during natural sleep-wakefulness and prolonged wakefulness: an in vivo microdialysis study. Neuroscience, 2002.113(3): p. 663-70.
90. Westerink, B.H., et al., Evidence for activation of histamine H3 autoreceptors during handling stress in the prefrontal cortex of the rat. Synapse, 2002.43(4): p. 238-43.
91. Huang, Z.L., et al., Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A, 2001. 98(17): p. 9965-70.
92. Masaki, T., et al., Targeted disruption of histamine Hl-receptor attenuates regulatory effects of leptin on feeding, adiposity, and UCP family in mice. Diabetes, 2001. 50(2): p. 385-91.
93. Knigge, U., et al., Histaminergic and catecholaminergic interactions in the central regulation of vasopressin and oxytocin secretion. Endocrinology, 1999. 140(8): p. 3713-9.
94. Haas, H.L., P. Wolf, and J.C. Nussbaumer, Histamine: action on supraoptic and other hypothalamic neurones of the cat. Brain Res, 1975. 88(1): p. 166-70.
95. Armstrong, W.E. and C.D. Sladek, Evidence for excitatory actions of histamine on supraoptic neurons in vitro: mediation by an H1-type receptor. Neuroscience, 1985.16(2): p. 307-22.
96. Bhargava, K.P., et al., Mechanism of histamine-induced antidiuretic response. Br J Pharmacol, 1973.47(4): p. 700-6.
97. Tuomisto, L., L. Eriksson, and F. Fyhrquist, Vasopressin release by histamine in the conscious goat. Eur J Pharmacol, 1980. 63(1): p. 15-24.
98. Toyota, H., et al., Behavioral characterization of mice lacking histamine H(3) receptors. Mol Pharmacol, 2002.62(2): p. 389-97.
99. Inoue, I., et al., Characteristics of the mouse genomic histamine H1 receptor gene. Genomics, 1996.36(1): p. 178-81.
100. Inoue, I., et al., Impaired locomotor activity and exploratory behavior in mice lacking histamine H1 receptors. Proc Natl Acad Sci U S A, 1996. 93(23): p. 13316-20.
101. Malmberg, K., L. Ryden, and H. Wedel, Calcium antagonists, appropriate therapy for diabetic patients with hypertension? Eur Heart J, 1998. 19(9): p. 1269-72.
102. Hough, L.B. and J.W. Nalwalk, Inhibition of morphine antinociception by centrally administered histamine H2 receptor antagonists. Eur J Pharmacol, 1992. 215(1): p. 69-74.
103. Airaksinen, M.S., et al., Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains. Neuroscience, 1991.44(2): p. 465-81.
104. Nakamura, S., et al., Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer's disease. Neurosci Lett, 1993.151(2): p. 196-9.
105. Panula, P., et al., Neuronal histamine deficit in Alzheimer's disease. Neuroscience, 1998. 82(4): p. 993-7.
106. Chen, Z., et al., Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats. Brain Res, 1999. 839(1): p. 186-9.
107. Chen, Z. and C. Kamei, Facilitating effects of histamine on spatial memory deficit induced by scopolamine in rats. Acta Pharmacol Sin, 2000. 21(9): p. 814-8.
108. Huang, Y.W., et al., Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by 8-arm radial maze in SD rats. Acta Pharmacol Sin, 2003.24(12): p. 1270-6.
109. Huang, Y.W., et al., Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluated by radial maze in Sprague-Dawley rats. Behav Brain Res, 2004.151(1-2): p. 287-93.
110. Chen, Z. and Y.J. Shen, Effects of brain histamine on memory deficit induced by nucleus basalis-lesion in rats. Acta Pharmacol Sin, 2002.23(1): p. 66-70.
111. Nakamura, S., et al., Large neurons in the tuberomammillary nucleus in patients with Parkinson's disease and multiple system atrophy. Neurology, 1996. 46(6): p. 1693-6.
112. Garbarg, M., et al., Brain histidine decarboxylase activity in Parkinson's disease. Lancet, 1983.1(8314-5): p. 74-5.
113. Rinne, J.O., et al., Increased brain histamine levels in Parkinson's disease but not in multiple system atrophy. J Neurochem, 2002. 81(5): p. 954-60.
114. Anichtchik, O.V., et al., Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease. Neurobiol Dis, 2001. 8(4): p. 707-16.
115. Ryu, J.H., K. Yanai, and T. Watanabe, Marked increase in histamine H3 receptors in the striatum and substantia nigra after 6-hydroxydopamine-induced denervation of dopaminergic neurons: an autoradiographic study. Neurosci Lett, 1994.178(1): p. 19-22.
116. Anichtchik, O.V., et al., Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats. Eur J Neurosci, 2000.12(11): p. 3823-32.
117. Adachi, N., R. Oishi, and K. Saeki, Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem, 1991.57(1): p. 61-6.
118. Yokoyama, H., et al., Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of alpha-fluoromethylhistidine and metoprine. Naunyn Schmiedebergs Arch Pharmacol, 1992.346(1): p. 40-5.
119. Chen, Z., et al., Chemical kindling induced by pentylenetetrazol in histamine H(l) receptor gene knockout mice (H(l)KO), histidine decarboxylase-deficient mice (HDC(-/-)) and mast cell-deficient W/W(v) mice. Brain Res, 2003. 968(1): p. 162-6.
120. Jin, C.L., et al., Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res, 2007. 73(3): p. 250-8.
121. Vohora, D., S.N. Pal, and K.K. Pillai, Histamine and selective H3-receptor ligands: a possible role in the mechanism and management of epilepsy. Pharmacol Biochem Behav, 2001. 68(4): p. 735-41.
122. Zhang, L.S., et al., Effects of endogenous histamine on seizure development of pentylenetetrazole-induced kindling in rats. Pharmacology, 2003. 69(1): p. 27-32.
123. Zhang, L., et al., Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats. Eur J Pharmacol, 2003.482(1-3): p. 169-75.
124. Li, Q., et al., Histidine enhances carbamazepine action against seizures and improves spatial memory deficits induced by chronic transauricular kindling in rats. Acta Pharmacol Sin, 2005.26(11): p. 1297-302.
2. Panula, P., H.Y. Yang, and E. Costa, Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A, 1984. 81(8): p. 2572-6.
3. Watanabe, T., et al., Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res, 1984. 295(1): p. 13-25.
4. Schwartz, J.C., et al., Histaminergic transmission in the mammalian brain. Physiol Rev, 1991. 71(1): p. 1-51.
5. Bouthenet, M.L., et al., A detailed mapping of histamine H1-receptors in guinea-pig central nervous system established by autoradiography with [125I]iodobolpyramine. Neuroscience, 1988. 26(2): p. 553-600.
6. Martinez-Mir, M.I., et al., Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res, 1990. 526(2): p. 322-7.
7. Morisset, S., et al., High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature, 2000. 408(6814): p. 860-4.
8. Arrang, J.M., et al., Molecular and functional diversity of histamine receptor subtypes. Ann N Y Acad Sci, 1995.757: p. 314-23.
9. Zhang, L., et al., Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats. Eur J Pharmacol, 2003.482(1-3): p. 169-75.
10. Jin, C.L., et al., Lesion of the tuberomammiUary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res, 2007. 73(3): p. 250-8.
11. Huang, Y.W., et al., Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluated by radial maze in Sprague-Dawley rats. Behav Brain Res, 2004.151(1-2): p. 287-93.
12. Chen, Z., et al., Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats. Brain Res, 1999. 839(1): p. 186-9.
13. Adachi, N., R. Oishi, and K. Saeki, Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem, 1991.57(1): p. 61-6.
14. Kamei, C, Y. Okumura, and K. Tasaka, Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology (Berl), 1993. 111(3): p. 376-82.
15. Alvarez, E.O. and A.M. Banzan, Hippocampus and learning: possible role of histamine receptors. Medicina (B Aires), 1996. 56(2): p. 155-60.
16. Sakai, N., et al., Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels. Life Sci, 1998. 62(11): p. 989-94.
17. Chen, Z., Y. Sugimoto, and C. Kamei, Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav, 1999. 64(3): p. 513-8.
18. Hasenohrl, R.U., K. Weth, and J.P. Huston, Intraventricular infusion of the histamine H(l) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res, 1999.128(4): p. 435-40.
19. Taga, C, et al., Effects of vasopressin on histamine H(1) receptor antagonist-induced spatial memory deficits in rats. Eur J Pharmacol, 2001. 423(2-3): p. 167-70.
20. Yanai, K., et al., Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 1998. 87(2): p. 479-87.
21. Yanai, K., et al., Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci, 1998. 62(17-18): p. 1607-10.
22. Flood, J.F., K. Uezu, and J.E. Morley, Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing. Psychopharmacology (Berl), 1998.140(3): p. 279-84.
23. Onodera, K., et al., Neuropharmacology of the histaminergic neuron system in the brain and its relationship with behavioral disorders. Prog Neurobiol, 1994. 42(6): p. 685-702.
24. Blandina, P., et al., Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br J Pharmacol, 1996. 119(8): p. 1656-64.
25. Rubio, S., et al., Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res, 2002.129(1-2): p. 77-82.
26. Watanabe, T., et al., Pharmacology of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol Sci, 1990. 11(9): p. 363-7.
27. Onodera, K.., A. Yamatodani, and T. Watanabe, Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats. Methods Find Exp Clin Pharmacol, 1992. 14(2): p. 97-105.
28. Hill, S.J., et al., International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev, 1997.49(3): p. 253-78.
29. Haas, H. and P. Panula, The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci, 2003.4(2): p. 121-30.
30. Ohtsu, H., et al., Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett, 2001.502(1-2): p. 53-6.
31. Kubota, Y., et al., Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice. J Neurochem, 2002. 83(4): p. 837-45.
32. Iwabuchi, K., et al., Methamphetamine and brain histamine: a study using histamine-related gene knockout mice. Ann N Y Acad Sci, 2004. 1025: p. 129-34.
33. Dere, E., et al., Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci, 2004. 20(4): p. 1051-8.
34. Bliss, T.V. and G.L. Collingridge, A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 1993.361(6407): p. 31-9.
35. Nakazawa, K., et al., NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci, 2004. 5(5): p. 361-72.
36. Bliss, T.V. and A.R. Gardner-Medwin, Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path. J Physiol, 1973. 232(2): p. 357-74.
37. Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus. Science, 1993.261(5117): p. 104-6.
38. Vorobjev, V.S., et al., Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron, 1993.11(5): p. 837-44.
39. Williams, K., Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 1994. 46(3): p. 531-41.
40. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CAl of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
41. Payne, G.W. and R.S. Neuman, Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses. Br J Pharmacol, 1997. 121(2): p. 199-204.
42. Selbach, O., R.E. Brown, and H.L. Haas, Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology, 1997. 36(11-12): p. 1539-48.
43. Brown, R.E. and H.L. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus. J Physiol, 1999.515 (Pt 3): p. 777-86.
44. Kim, J.J. and M.S. Fanselow, Modality-specific retrograde amnesia of fear. Science, 1992. 256(5057): p. 675-7.
45. Phillips, R.G. and J.E. LeDoux, Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci, 1992. 106(2): p. 274-85.
1. Zhang, L., et al., Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats. Eur J Pharmacol, 2003.482(1-3): p. 169-75.
2. Jin, C.L., et al., Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res, 2007. 73(3): p. 250-8.
3. Huang, Y.W., et al., Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluated by radial maze in Sprague-Dawley rats. Behav Brain Res, 2004.151(1-2): p. 287-93.
4. Chen, Z., et al., Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats. Brain Res, 1999. 839(1): p. 186-9.
5. Adachi, N., R. Oishi, and K. Saeki, Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem, 1991.57(1): p. 61-6.
6. Flood, J.F., K. Uezu, and J.E. Morley, Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing. Psychopharmacology (Berl), 1998.140(3): p. 279-84.
7. Sakai, N., et al., Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels. Life Sci, 1998. 62(11): p. 989-94.
8. Yanai, K., et al., Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 1998.87(2): p. 479-87.
9. Yanai, K., et al., Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci, 1998. 62(17-18): p. 1607-10.
10. Chen, Z., Y. Sugimoto, and C. Kamei, Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav, 1999. 64(3): p. 513-8.
11. Hasenohrl, R.U., KL Weth, and J.P. Huston, Intraventricular infusion of the histamine H(1) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res, 1999.128(4): p. 435-40.
12. Taga, C, et al., Effects of vasopressin on histamine H(l) receptor antagonist-induced spatial memory deficits in rats. Eur J Pharmacol, 2001. 423(2-3): p. 167-70.
13. Rubio, S., et al., Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res, 2002.129(1-2): p. 77-82.
14. Watanabe, T., et al., Pharmacology of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol Sci, 1990.11(9): p. 363-7.
15. Onodera, K., A. Yamatodani, and T. Watanabe, Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats. Methods Find Exp Clin Pharmacol, 1992.14(2): p. 97-105.
16. Hill, S J., et al., International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev, 1997.49(3): p. 253-78.
17. Haas, H. and P. Panula, The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci, 2003. 4(2): p. 121-30.
18. Kim, J J. and M.S. Fanselow, Modality-specific retrograde amnesia of fear. Science, 1992. 256(5057): p. 675-7.
19. Phillips, R.G. and J.E. LeDoux, Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci, 1992. 106(2): p. 274-85.
20. Toyoda, M., H. Saito, and N. Matsuki, Nitric oxide but not carbon monoxide is involved in spatial learning of mice. Jpn J Pharmacol, 1996.71(3): p. 205-11.
21. Glowinski, J. and L.L. Iversen, Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem, 1966.13(8): p. 655-69.
22. Zhu, L.J., et al., Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. Neurosci Lett, 2004.356(1): p. 53-6.
23. Ohtsu, H., et al., Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett, 2001.502(1-2): p. 53-6.
24. Parmentier, R., et al., Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci, 2002. 22(17): p. 7695-711.
25. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CA1 of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
26. Dere, E., et al., Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci, 2004.20(4): p. 1051-8.
27. Acevedo, S.F., et al., Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice. Brain Res, 2006.1071(1): p. 113-23.
28. Blanchard, R J. and D.C. Blanchard, Crouching as an index of fear. J Comp Physiol Psychol, 1969.67(3): p. 370-5.
29. LeDoux, J.E., Brain mechanisms of emotion and emotional learning. Curr Opin Neurobiol, 1992.2(2): p. 191-7.
30. Anagnostaras, S.G., G.D. Gale, and M.S. Fanselow, Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus, 2001.11(1): p. 8-17.
31. Jorgensen, E.A., et al., Increased susceptibility to diet-induced obesity in histamine-deficient mice. Neuroendocrinology, 2006.83(5-6): p. 289-94.
32. Morris, R.G., et al., Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos Trans R Soc Lond B Biol Sci, 2003.358(1432): p. 773-86.
33. Hirsh, R., The hippocampus and contextual retrieval of information from memory: a theory. Behav Biol, 1974.12(4): p. 421-44.
34. McClelland, J.L., B.L. McNaughton, and R.C. O'Reilly, Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev, 1995.102(3): p. 419-57.
35. Squire, L.R., R.E. Clark, and B.J. Knowlton, Retrograde amnesia. Hippocampus, 2001.11(1): p. 50-5.
36. Jensen, R.A., et al., Benzodiazepines alter acquisition and retention of an inhibitory avoidance response in mice. Psychopharmacology (Berl), 1979. 64(1): p. 125-6.
37. Martinez, J.L., Jr., et al., ACTH4-9 analog (ORG 2766) facilitates acquisition of an inhibitory avoidance response in rats. Pharmacol Biochem Behav, 1979. 10(1): p. 145-7.
38. Passani, M.B., et al., Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala. Eur J Neurosci, 2001.14(9): p. 1522-32.
39. Cangioli, I., et al., Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release. Eur J Neurosci, 2002.16(3): p. 521-8.
40. Baldi, E., et al., The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat. Neuropharmacology, 2005.48(2): p. 246-51.
41. de Almeida, M.A. and I. Izquierdo, Memory facilitation by histamine. Arch Int Pharmacodyn Ther, 1986.283(2): p. 193-8.
42. de Almeida, M.A. and I. Izquierdo, Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch Int Pharmacodyn Ther, 1988.291: p. 202-7.
43. Kamei, C. and K. Tasaka, Effect of histamine on memory retrieval in old rats. Biol Pharm Bull, 1993.16(2): p. 128-32.
44. Alvarez, E.O. and A.M. Banzan, Effects of localized histamine microinjections into the hippocampal formation on the retrieval of a one-way active avoidance response in rats. J Neural Transm Gen Sect, 1995.101(1-3): p. 201-11.
45. Eidi, M., et al., Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2003.465(1-2): p. 91-6.
46. Huston, J.P., U. Wagner, and R.U. Hasenohrl, The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role. Behav Brain Res, 1997. 83(1-2): p. 97-105.
47. Zarrindast, M.R., et al., Effects of histamine and opioid systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2002.452(2): p. 193-7.
1. Bliss, T.V. and G.L. Collingridge, A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 1993.361(6407): p. 31-9.
2. Nakazawa, K., et al., NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci, 2004.5(5): p. 361-72.
3. Bliss, T.V. and A.R. Gardner-Medwin, Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path. J Physiol, 1973.232(2): p. 357-74.
4. Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus. Science, 1993.261(5117): p. 104-6.
5. Vorobjev, V.S., et al., Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron, 1993.11(5): p. 837-44.
6. Williams, K., Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 1994. 46(3): p. 531-41.
7. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CAl of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
8. Payne, G.W. and R.S. Neuman, Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses. Br J Pharmacol, 1997. 121(2): p. 199-204.
9. Selbach, O., R.E. Brown, and H.L. Haas, Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology, 1997. 36(11-12): p. 1539-48.
10. Brown, R.E. and H.L. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyms. J Physiol, 1999. 515 (Pt 3): p. 777-86.
11. Debanne, D., et al., Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release. J Physiol, 1996. 491 (Pt 1): p. 163-76.
12. Foster, T.C. and B.L. McNaughton, Long-term enhancement of CA1 synaptic transmission is due to increased quantal size, not quantal content. Hippocampus, 1991.1(1): p. 79-91.
13. Hess, G., U. Kuhnt, and L.L. Voronin, Quantal analysis of paired-pulse facilitation in guinea pig hippocampal slices. Neurosci Lett, 1987. 77(2): p. 187-92.
14. Del Castillo, J. and B. Katz, Statistical factors involved in neuromuscular facilitation and depression. J Physiol, 1954. 124(3): p. 574-85.
15. Zhao, M.G., et al., Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron, 2005. 47(6): p. 859-72.
16. Lynch, G.S., T. Dunwiddie, and V. Gribkoff, Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature, 1977. 266(5604): p. 737-9.
17. Linden, D.J. and J.A. Connor, Long-term synaptic depression. Annu Rev Neurosci, 1995. 18: p. 319-57.
18. Garcia, M., et al., Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience, 1997. 80(1): p. 241-9.
19. Lynch, M.A., Long-term potentiation and memory. Physiol Rev, 2004. 84(1): p. 87-136.
20. Dere, E., et al., Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover. Learn Mem, 2003.10(6): p. 510-9.
21. Liu, L., et al., Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science, 2004.304(5673): p. 1021-4.
22. Frey, U., et al., The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CAl region in vitro. Neurosci Lett, 1991.129(1): p. 111-4.
23. Huang, Y.Y. and E.R. Kandel, D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CAl region of the hippocampus. Proc Natl Acad Sci U S A, 1995. 92(7): p. 2446-50.
24. Lemon, N. and D. Manahan-Vaughan, Dopamine D1/D5 receptors gate the acquisition of novel information through hippocampal long-term potentiation and long-term depression. J Neurosci, 2006. 26(29): p. 7723-9.
25. Gao, C, X. Sun, and M.E. Wolf, Activation of Dl dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons. J Neurochem, 2006.
26. Doreulee, N., et al., Histamine H(3) receptors depress synaptic transmission in the corticostriatal pathway. Neuropharmacology, 2001.40(1): p. 106-13.
27. Parnas, H., I. Parnas, and L.A. Segel, On the contribution of mathematical models to the understanding of neurotransmitter release. Int Rev Neurobiol, 1990.32: p. 1-50.
28. Li, Z., et al., Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CAl area in vivo. Hippocampus, 2005.15(6): p. 815-24.
29. Barnes, C, et al., LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J. Neurosci., 1994.14(10): p. 5793-5806.
30. McNaughton, B.L., et al., Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information. J Neurosci, 1986.6(2): p. 563-71.
31. Moser, E.I., et al., Impaired spatial learning after saturation of long-term potentiation. Science, 1998.281(5385): p. 2038-42.
32. Gruart, A., M.D. Munoz, and J.M. Delgado-Garcia, Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci, 2006.26(4): p. 1077-87.
1. Garbarg, M., et al., Histaminergic pathway in rat brain evidenced by lesions of the medial forebrain bundle. Science, 1974.186(4166): p. 833-5.
2. Panula, P., H.Y. Yang, and E. Costa, Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A, 1984. 81(8): p. 2572-6.
3. Watanabe, T., et al., Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res, 1984.295(1): p. 13-25.
4. Garbarg, M., et al., Dual localization of histamine in an ascending neuronal pathway and in non-neuronal cells evidenced by lesions in the lateral hypothalamic area. Brain Res, 1976.106(2): p. 333-48.
5. Dropp, J.J., Mast cells in the human brain. Acta Anat (Basel), 1979. 105(4): p. 505-13.
6. Theoharides, T.C., Mast cells: the immune gate to the brain. Life Sci, 1990. 46(9): p. 607-17.
7. Hu, W., et al., Effect of cerebral ischemia on brain mast cells in rats. Brain Res, 2004.1019(1-2): p. 275-80.
8. Hough, L.B., Cellular localization and possible functions for brain histamine: recent progress. Prog Neurobiol, 1988.30(6): p. 469-505.
9. Prell, G.D. and J.P. Green, Histamine as a neuroregulator. Annu Rev Neurosci, 1986.9: p. 209-54.
10. Lin, J.S., et al., Immunohistochemical evidence for the presence of type B monoamine oxidase in histamine-containing neurons in the posterior hypothalamus of cats. Neurosci Lett, 1991.128(1): p. 61-5.
11. Schwartz, J.C., et al., Histaminergic transmission in the mammalian brain. Physiol Rev, 1991.71(1): p. 1-51.
12. Arrang, J.M., M. Garbarg, and J.C. Schwartz, Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature, 1983. 302(5911): p. 832-7.
13. Itoh, Y., et al., Characterization of histamine release from the rat hypothalamus as measured by in vivo microdialysis. J Neurochem, 1991.56(3): p. 769-74.
14. Prast, H., et al., In vivo modulation of histamine release by autoreceptors and muscarinic acetylcholine receptors in the rat anterior hypothalamus. Naunyn Schmiedebergs Arch Pharmacol, 1994.350(6): p. 599-604.
15. Panula, P., et al., Histamine-immunoreactive nerve fibers in the rat brain. Neuroscience, 1989.28(3): p. 585-610.
16. Kaslin, J. and P. Panula, Comparative anatomy of the histaminergic and other aminergic systems in zebrafish (Danio rerio). J Comp Neurol, 2001. 440(4): p. 342-77.
17. Vincent, S.R., et al., Hypothalamic gamma-aminobutyric acid neurons project to the neocortex. Science, 1983.220(4603): p. 1309-11.
18. Takeda, N., et al., Immunohistochemical evidence for the coexistence of histidine decarboxylase-like and glutamate decarboxylase-like immunoreactivities in nerve cells of the magnocellular nucleus of the posterior hypothalamus of rats. Proc Natl Acad Sci U S A, 1984. 81(23): p. 7647-50.
19. Senba, E., P.E. Daddona, and J.I. Nagy, Adenosine deaminase-containing neurons in the olfactory system of the rat during development. Brain Res Bull, 1987.18(5): p. 635-48.
20. Ericson, H., C. Kohler, and A. Blomqvist, GABA-like immunoreactivity in the tuberomammillary nucleus: an electron microscopic study in the rat. J Comp Neurol, 1991.305(3): p. 462-9.
21. Airaksinen, M.S., et al., Multiple neurotransmitters in the tuberomammillary nucleus: comparison of rat, mouse, and guinea pig. J Comp Neurol, 1992.323(1): p. 103-16.
22. Staines, W.A., et al., Neuronal colocalization of adenosine deaminase, monoamine oxidase, galanin and 5-hydroxytryptophan uptake in the tuberomammillary nucleus of the rat. Brain Res Bull, 1986.17(3): p. 351-65.
23. Nguyen, T., et al., Discovery of a novel member of the histamine receptor family. Mol Pharmacol, 2001.59(3): p. 427-33.
24. Bouthenet, M.L., et al., A detailed mapping of histamine H1-receptors in guinea-pig central nervous system established by autoradiography with [125I]iodobolpyramine. Neuroscience, 1988.26(2): p. 553-600.
25. Martinez-Mir, M.I., et al., Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res, 1990. 526(2): p. 322-7.
26. Leurs, R., et al., H3 receptor gene is cloned at last. Trends Pharmacol Sci, 2000. 21(1): p. 11-2.
27. Yamashita, M., et al., Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc Natl Acad Sci U S A, 1991. 88(24): p. 11515-9.
28. Leurs, R., et al., Guinea pig histamine H1 receptor. II. Stable expression in Chinese hamster ovary cells reveals the interaction with three major signal transduction pathways. J Neurochem, 1994. 62(2): p. 519-27.
29. Black, J.W., et al., Definition and antagonism of histamine H 2 -receptors. Nature, 1972.236(5347): p. 385-90.
30. Traiffort, E., et al., The guinea pig histamine H2 receptor: gene cloning, tissue expression and chromosomal localization of its human counterpart. Biochem Biophys Res Commun, 1995. 211(2): p. 570-7.
31. Coge, F., et al., Genomic organization and characterization of splice variants of the human histamine H3 receptor. Biochem J, 2001. 355(Pt 2): p. 279-88.
32. Drutel, G., et al., Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol Pharmacol, 2001.59(1): p. 1-8.
33. Lovenberg, T.W., et al., Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol, 1999.55(6): p. 1101-7.
34. Morisset, S., et al., High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature, 2000.408(6814): p. 860-4.
35. Arrang, J.M., et al., Molecular and functional diversity of histamine receptor subtypes. Ann N Y Acad Sci, 1995.757: p. 314-23.
36. Richelson, E., Histamine H1 receptor-mediated guanosine 3',5'-monophosphate formation by cultured mouse neuroblastoma cells. Science, 1978. 201(4350): p. 69-71.
37. Baudry, M., M.P. Martres, and J.C. Schwartz, H1 and H2 receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices. Nature, 1975.253(5490): p. 362-4.
38. Daum, P.R., S.J. Hill, and J.M. Young, Histamine H1-agonist potentiation of adenosine-stimulated cyclic AMP accumulation in slices of guinea-pig cerebral cortex: comparison of response and binding parameters. Br J Pharmacol, 1982. 77(2): p. 347-57.
39. Chang, R.S., V.T. Tran, and S.H. Snyder, Heterogeneity of histamine H1-receptors: species variations in [3H]mepyramine binding of brain membranes. J Neurochem, 1979.32(6): p. 1653-63.
40. Palacios, J.M., J.K. Wamsley, and M.J. Kuhar, The distribution of histamine Hl-receptors in the rat brain: an autoradiographic study. Neuroscience, 1981. 6(1): p. 15-37.
41. Selbach, O., R.E. Brown, and H.L. Haas, Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology, 1997. 36(11-12): p. 1539-48.
42. Brown, R.E., D.R. Stevens, and H.L. Haas, The physiology of brain histamine. Prog Neurobiol, 2001.63(6): p. 637-72.
43. Yanovsky, Y. and H.L. Haas, Histamine increases the bursting activity of pyramidal cells in the CA3 region of mouse hippocampus. Neurosci Lett, 1998. 240(2): p. 110-2.
44. Traiffort, E., et al., Pharmacological characterization and autoradiographic localization of histamine H2 receptors in human brain identified with [125I]iodoaminopotentidine. J Neurochem, 1992.59(1): p. 290-9.
45. Vizuete, M.L., et al., Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain. Neuroscience, 1997. 80(2): p. 321-43.
46. Brown, R.E. and K.G. Reymann, Histamine H3 receptor-mediated depression of synaptic transmission in the dentate gyrus of the rat in vitro. J Physiol, 1996.496 (Pt 1): p. 175-84.
47. Garcia, M., et al., Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience, 1997.80(1): p. 241-9.
48. Schlicker, E., et al., Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors. Naunyn Schmiedebergs Arch Pharmacol, 1989. 340(6): p. 633-8.
49. Schlicker, E., et al., Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. J Neural Transm Gen Sect, 1993. 93(1): p. 1-10.
50. Arrang, J.M., G. Drutel, and J.C. Schwartz, Characterization of histamine H3 receptors regulating acetylcholine release in rat entorhinal cortex. Br J Pharmacol, 1995.114(7): p. 1518-22.
51. Schlicker, E., R. Betz, and M. Gothert, Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol, 1988.337(5): p. 588-90.
52. Hill, SJ., et al., International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev, 1997. 49(3): p. 253-78.
53. Kamei, C, Y. Okumura, and K. Tasaka, Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology (Berl), 1993. 111(3): p. 376-82.
54. Alvarez, E.O. and A.M. Banzan, Hippocampus and learning: possible role of histamine receptors. Medicina (B Aires), 1996.56(2): p. 155-60.
55. Sakai, N., et al., Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino add levels. Life Sci, 1998. 62(11): p. 989-94.
56. Chen, Z., Y. Sugimoto, and C. Kamei, Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav, 1999. 64(3): p. 513-8.
57. Hasenohrl, R.U., K. Weth, and J.P. Huston, Intraventricular infusion of the histamine H(l) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res, 1999.128(4): p. 435-40.
58. Taga, C., et al., Effects of vasopressin on histamine H(l) receptor antagonist-induced spatial memory deficits in rats. Eur J Pharmacol, 2001. 423(2-3): p. 167-70.
59. Yanai, K., et al., Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 1998.87(2): p. 479-87.
60. Yanai, K., et al., Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci, 1998. 62(17-18): p. 1607-10.
61. Flood, J.F., K. Uezu, and J.E. Morley, Effect of histamine H2 and H3 receptor modulation in the septum on post-training memory processing. Psychopharmacology (Berl), 1998.140(3): p. 279-84.
62. Onodera, K., et al., Neuropharmacology of the histaminergic neuron system in the brain and its relationship with behavioral disorders. Prog Neurobiol, 1994. 42(6): p. 685-702.
63. Blandina, P., et al., Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br J Pharmacol, 1996. 119(8): p. 1656-64.
64. Rubio, S., et al., Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res, 2002.129(1-2): p. 77-82.
65. de Almeida, M.A. and I. Izquierdo, Memory facilitation by histamine. Arch Int Pharmacodyn Ther, 1986.283(2): p. 193-8.
66. de Almeida, M.A. and I. Izquierdo, Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch Int Pharmacodyn Ther, 1988. 291: p. 202-7.
67. Kamei, C. and K. Tasaka, Effect of histamine on memory retrieval in old rats. Biol Pharm Bull, 1993.16(2): p. 128-32.
68. Alvarez, E.O. and A.M. Banzan, Effects of localized histamine microinjections into the hippocampal formation on the retrieval of a one-way active avoidance response in rats. J Neural Transm Gen Sect, 1995.101(1-3): p. 201-11.
69. Eidi, M., et al., Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2003. 465(1-2): p. 91-6.
70. Huston, J.P., U. Wagner, and R.U. Hasenohrl, The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role. Behav Brain Res, 1997.83(1-2): p. 97-105.
71. Zarrindast, M.R., et al., Effects of histamine and opioid systems on memory retention of passive avoidance learning in rats. Eur J Pharmacol, 2002. 452(2): p. 193-7.
72. Watanabe, T., et al., Pharmacology of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol Sci, 1990. 11(9): p. 363-7.
73. Onodera, K., A. Yamatodani, and T. Watanabe, Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats. Methods Find Exp Clin Pharmacol, 1992.14(2): p. 97-105.
74. Haas, H. and P. Panula, The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci, 2003.4(2): p. 121-30.
75. Dere, E., et al., Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci, 2004.20(4): p. 1051-8.
76. Acevedo, S.F., et al., Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice. Brain Res, 2006. 1071(1): p. 113-23.
77. Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus. Science, 1993.261(5117): p. 104-6.
78. Vorobjev, V.S., et al., Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron, 1993.11(5): p. 837-44.
79. Williams, K., Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 1994. 46(3): p. 531-41.
80. Brown, R.E., et al., Histaminergic modulation of synaptic plasticity in area CA1 of rat hippocampal slices. Neuropharmacology, 1995.34(2): p. 181-90.
81. Payne, G.W. and R.S. Neuman, Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses. Br J Pharmacol, 1997. 121(2): p. 199-204.
82. Brown, R.E. and H.L. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus. J Physiol, 1999.515 (Pt 3): p. 777-86.
83. Lin, J.S., et al., A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. Brain Res, 1989.479(2): p. 225-40.
84. Parmentier, R., et al., Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci, 2002. 22(17): p. 7695-711.
85. Mochizuki, T., et al., In vivo release of neuronal histamine in the hypothalamus of rats measured by microdialysis. Naunyn Schmiedebergs Arch Pharmacol, 1991.343(2): p. 190-5.
86. Cecchi, M., et al., Cortical acetylcholine release elicited by stimulation of histamine H1 receptors in the nucleus basalis magnocellularis: a dual-probe microdialysis study in the freely moving rat. Eur J Neurosci, 2001. 13(1): p. 68-78.
87. Brown, R.E., et al., Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci, 2002.22(20): p. 8850-9.
88. Cangioli, I., et al., Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release. Eur J Neurosci, 2002.16(3): p. 521-8.
89. Strecker, R.E., et al., Extracellular histamine levels in the feline preoptic/anterior hypothalamic area during natural sleep-wakefulness and prolonged wakefulness: an in vivo microdialysis study. Neuroscience, 2002.113(3): p. 663-70.
90. Westerink, B.H., et al., Evidence for activation of histamine H3 autoreceptors during handling stress in the prefrontal cortex of the rat. Synapse, 2002.43(4): p. 238-43.
91. Huang, Z.L., et al., Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A, 2001. 98(17): p. 9965-70.
92. Masaki, T., et al., Targeted disruption of histamine Hl-receptor attenuates regulatory effects of leptin on feeding, adiposity, and UCP family in mice. Diabetes, 2001. 50(2): p. 385-91.
93. Knigge, U., et al., Histaminergic and catecholaminergic interactions in the central regulation of vasopressin and oxytocin secretion. Endocrinology, 1999. 140(8): p. 3713-9.
94. Haas, H.L., P. Wolf, and J.C. Nussbaumer, Histamine: action on supraoptic and other hypothalamic neurones of the cat. Brain Res, 1975. 88(1): p. 166-70.
95. Armstrong, W.E. and C.D. Sladek, Evidence for excitatory actions of histamine on supraoptic neurons in vitro: mediation by an H1-type receptor. Neuroscience, 1985.16(2): p. 307-22.
96. Bhargava, K.P., et al., Mechanism of histamine-induced antidiuretic response. Br J Pharmacol, 1973.47(4): p. 700-6.
97. Tuomisto, L., L. Eriksson, and F. Fyhrquist, Vasopressin release by histamine in the conscious goat. Eur J Pharmacol, 1980. 63(1): p. 15-24.
98. Toyota, H., et al., Behavioral characterization of mice lacking histamine H(3) receptors. Mol Pharmacol, 2002.62(2): p. 389-97.
99. Inoue, I., et al., Characteristics of the mouse genomic histamine H1 receptor gene. Genomics, 1996.36(1): p. 178-81.
100. Inoue, I., et al., Impaired locomotor activity and exploratory behavior in mice lacking histamine H1 receptors. Proc Natl Acad Sci U S A, 1996. 93(23): p. 13316-20.
101. Malmberg, K., L. Ryden, and H. Wedel, Calcium antagonists, appropriate therapy for diabetic patients with hypertension? Eur Heart J, 1998. 19(9): p. 1269-72.
102. Hough, L.B. and J.W. Nalwalk, Inhibition of morphine antinociception by centrally administered histamine H2 receptor antagonists. Eur J Pharmacol, 1992. 215(1): p. 69-74.
103. Airaksinen, M.S., et al., Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains. Neuroscience, 1991.44(2): p. 465-81.
104. Nakamura, S., et al., Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer's disease. Neurosci Lett, 1993.151(2): p. 196-9.
105. Panula, P., et al., Neuronal histamine deficit in Alzheimer's disease. Neuroscience, 1998. 82(4): p. 993-7.
106. Chen, Z., et al., Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats. Brain Res, 1999. 839(1): p. 186-9.
107. Chen, Z. and C. Kamei, Facilitating effects of histamine on spatial memory deficit induced by scopolamine in rats. Acta Pharmacol Sin, 2000. 21(9): p. 814-8.
108. Huang, Y.W., et al., Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by 8-arm radial maze in SD rats. Acta Pharmacol Sin, 2003.24(12): p. 1270-6.
109. Huang, Y.W., et al., Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluated by radial maze in Sprague-Dawley rats. Behav Brain Res, 2004.151(1-2): p. 287-93.
110. Chen, Z. and Y.J. Shen, Effects of brain histamine on memory deficit induced by nucleus basalis-lesion in rats. Acta Pharmacol Sin, 2002.23(1): p. 66-70.
111. Nakamura, S., et al., Large neurons in the tuberomammillary nucleus in patients with Parkinson's disease and multiple system atrophy. Neurology, 1996. 46(6): p. 1693-6.
112. Garbarg, M., et al., Brain histidine decarboxylase activity in Parkinson's disease. Lancet, 1983.1(8314-5): p. 74-5.
113. Rinne, J.O., et al., Increased brain histamine levels in Parkinson's disease but not in multiple system atrophy. J Neurochem, 2002. 81(5): p. 954-60.
114. Anichtchik, O.V., et al., Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease. Neurobiol Dis, 2001. 8(4): p. 707-16.
115. Ryu, J.H., K. Yanai, and T. Watanabe, Marked increase in histamine H3 receptors in the striatum and substantia nigra after 6-hydroxydopamine-induced denervation of dopaminergic neurons: an autoradiographic study. Neurosci Lett, 1994.178(1): p. 19-22.
116. Anichtchik, O.V., et al., Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats. Eur J Neurosci, 2000.12(11): p. 3823-32.
117. Adachi, N., R. Oishi, and K. Saeki, Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem, 1991.57(1): p. 61-6.
118. Yokoyama, H., et al., Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of alpha-fluoromethylhistidine and metoprine. Naunyn Schmiedebergs Arch Pharmacol, 1992.346(1): p. 40-5.
119. Chen, Z., et al., Chemical kindling induced by pentylenetetrazol in histamine H(l) receptor gene knockout mice (H(l)KO), histidine decarboxylase-deficient mice (HDC(-/-)) and mast cell-deficient W/W(v) mice. Brain Res, 2003. 968(1): p. 162-6.
120. Jin, C.L., et al., Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res, 2007. 73(3): p. 250-8.
121. Vohora, D., S.N. Pal, and K.K. Pillai, Histamine and selective H3-receptor ligands: a possible role in the mechanism and management of epilepsy. Pharmacol Biochem Behav, 2001. 68(4): p. 735-41.
122. Zhang, L.S., et al., Effects of endogenous histamine on seizure development of pentylenetetrazole-induced kindling in rats. Pharmacology, 2003. 69(1): p. 27-32.
123. Zhang, L., et al., Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats. Eur J Pharmacol, 2003.482(1-3): p. 169-75.
124. Li, Q., et al., Histidine enhances carbamazepine action against seizures and improves spatial memory deficits induced by chronic transauricular kindling in rats. Acta Pharmacol Sin, 2005.26(11): p. 1297-302.