Review
The human histaminergic system in neuropsychiatric disorders

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Highlights

  • Neuronal histamine production shows a diurnal rhythm, but not in neurodegeneration.

  • The histaminergic system shows alterations in various neuropsychiatric disorders.

  • Animal models for these disorders only partly mimic these histaminergic alterations.

  • Thus, postmortem human brain material is crucial to study these disorders.

Histaminergic neurons are exclusively located in the hypothalamic tuberomamillary nucleus, from where they project to many brain areas. The histaminergic system is involved in basic physiological functions, such as the sleep–wake cycle, energy and endocrine homeostasis, sensory and motor functions, cognition, and attention, which are all severely affected in neuropsychiatric disorders. Here, we present recent postmortem findings on the alterations in this system in neuropsychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), depression, and narcolepsy. In addition, we highlight the need to validate animal models for these diseases and also for Tourette's syndrome (TS) in relation to alterations in the histaminergic system. Moreover, we discuss the potential for, and concerns over, the use of novel histamine 3 receptor (H3R) antagonists/inverse agonists as treatment for such disorders.

Section snippets

Human neuronal histaminergic system

The neuronal histaminergic system is involved in several functions, such as the sleep–wake cycle, energy and endocrine homeostasis, sensory and motor functions, cognition, and attention, all of which tend to be severely affected in neuropsychiatric disorders, such as PD, AD, HD, depression, and narcolepsy. This system has been the subject of several reviews 1, 2, 3, such as one by Haas et al., which mostly summarized animal experimental findings before 2008 [1] and two by Panula et al., one

Anatomy and properties of human TMN

Histaminergic neurons are exclusive to the hypothalamic TMN, which is located in the posterior hypothalamus (Figure 1A). The human TMN is characterized by its typical lipofuscin-laden neurons, with intense Nissl staining of the endoplasmic reticulum localized in the periphery of the cytoplasm, interspersed with the typical irregularities in the cell membrane (Figure 1B,C). Studies using either Nissl staining [10] or histamine immunoreactivity [11] to examine tissue from neurological and

Histamine receptors and metabolism

Given that the signaling and downstream pathways of the G protein-coupled histamine receptors and of histamine metabolism have been extensively reviewed elsewhere 1, 2, we briefly review their characteristics in human brain in Box 1.

Parkinson's disease

PD is characterized by distinctive motor symptoms, mainly caused by loss of dopaminergic neurons in SN, including: tremor at rest, bradykinesia, rigidity, flexed posture, loss of postural reflexes, and freezing of gait [30]. In one of the PD animal models [i.e., the 6-hydroxydopamine (6-OHDA)-lesioned rat], an increase in endogenous histamine appeared to enhance apomorphine-induced turning behavior and to increase the loss of tyrosine hydroxylase (TH) in the SN [31]. In addition, in this model,

Concluding remarks

The human histaminergic system shows diurnal fluctuations in the TMN, which is its production site. In addition, there are changes in expression levels of HDC, H1–4R, and HMT in various neuropsychiatric disorders that might be related to symptoms of these diseases. The animal models used for these disorders do not, or only partly, reflect the histaminergic changes in the human brain.

In the human postmortem PD brain, no indication was found for an activation of endogenous histamine production,

Acknowledgments

This work was supported by the Program of Introducing Talents of Discipline to Universities of China (Nr. B13026) to D.S. and A-M.B., and supported by Zhejiang University K.P. Chao's Hi-Tech Foundation for Scholars and Scientists to D.S. It was also supported by the China Scholarship Council for State Scholarship Fund [grant number (2007) 3020] to L.S. The work has been presented and awarded a Young Investigators Award by the European Histamine Research Society to L.S. L.S. is currently

Glossary

Radioactive in situ hybridization (ISH)
enables specific nucleic acid sequences to be detected in morphologically well-preserved tissue sections. This technique is widely used to detect the expression of specific genes at the mRNA level. When relative quantitative comparison between experimental groups is needed, radioactive ISH still holds an advantage of signal quantification on paraffin-embedded tissue sections, which have practical advantages for anatomically complex structures, such as the

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