The Histaminergic System in Neuropsychiatric Disorders

Histamine does not only modulate the immune response and inflammation, but also acts as a neurotransmitter in the mammalian brain. The histaminergic system plays a significant role in the maintenance of wakefulness, appetite regulation, cognition and arousal, which are severely affected in neuropsychiatric disorders. In this review, we first briefly describe the distribution of histaminergic neurons, histamine receptors and their intracellular pathways. Next, we comprehensively summarize recent experimental and clinical findings on the precise role of histaminergic system in neuropsychiatric disorders, including cell-type role and its circuit bases in narcolepsy, schizophrenia, Alzheimer’s disease, Tourette’s syndrome and Parkinson’s disease. Finally, we provide some perspectives on future research to illustrate the curative role of the histaminergic system in neuropsychiatric disorders.


Introduction
Neuropsychiatric disorders are a group of multifaceted diseases characterized by cognitive deficits, mental health symptoms and somatoform symptoms, including schizophrenia, depression, Alzheimer's disease, Parkinson's disease, etc. Neuropsychiatric disorders are chronic diseases beginning early in life and affecting patients across all age groups [1]. These conditions are a major public health challenge with highly prevalence, diminishing quality of life for millions of patients and their caregivers [2][3][4]. Although several approved treatments for neuropsychiatric disorders exist, the mechanisms are still incompletely understood and there are no highly-efficient therapeutic methods currently. Thus, it is urgent to illuminate the pathogenesis of neuropsychiatric disorders and develop new effective treatment methods.
It has been long known that histamine could trigger peripheral actions, such as allergic responses and gastric acid secretion via its receptors. However, the later extensive investigations discovered that histamine in the brain mediates diverse higher functions, including arousal, cognition and feeding, and have indicated the abnormalities in the histaminergic nervous system are closely related to neuropsychiatric disorders, including narcolepsy, schizophrenia, Alzheimer's disease, Tourette's syndrome and Parkinson's disease. Since the histaminergic system is a recently discovered neuromodulatory system with anatomically differences, and histamine is a kind of relatively moderate neurotransmitter, the histaminergic system has garnered less attention than other neurotransmitter systems such as glutamatergic system and GABAergic system. In the past few decades, the knowledge of histamine neurobiology has continued to expand. Even though the numerous clinical trials have been disappointing, the H 3 R antagonist pitolisant has been approved for the treatment of narcolepsy. With the development of neuroscientific techniques, advanced studies of histaminergic system will provide potential drug target for the treatment of neuropsychiatric disorders.

Histamine H 1 Receptor (H 1 R)
Histamine H 1 receptor (H 1 R) is widely distributed in the central nervous system, especially in the brain regions known to regulate arousal state and sleep-wakefulness, such as thalamus, cortex, cholinergic nuclei, locus coeruleus and raphe nucleus etc. [21,23]. The H 1 R (486-491 amino-acids) is encoded by a single structural gene on the long arm of chromosome 3. Intracellularly, the H 1 R is coupled to Gq/11 proteins and stimulates phospholipase C (PLC), resulting in the activation of neurons and astrocytes [24][25][26]. The activated PLC catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (PIP2) into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of stored Ca 2+ from intracellular stores into the cytoplasm and DAG mediates the activation of protein kinase C (PKC). Additionally, the activation of H 1 R also lead to the production of cyclic guanosine monophosphate(cGMP) and nitric oxide (NO) and increase the activity of phospholipase A2 (PLA2), which induces arachidonic acid formation [9,10].

Histamine H 2 Receptor (H 2 R)
Histamine H 2 receptor (H 2 R) is mainly expressed in several brain areas including basal ganglia, hippocampus, amygdala and cerebral cortex [21,27]. The H 2 R (359 amino-acids) is located on the chromosome 5 and contains 8 exons. The H 2 R is coupled to Gs proteins and then stimulates adenylyl cylase, inducing an increase in intracellular cyclic adenosine monophosphate (cAMP) production. The increase in cAMP activates protein kinase A (PKA), which in turn phosphorylates its target proteins in the cytosol, cell membrane or translocate to the nucleus, and then activate the cAMP response element-binding protein (CREB). H 2 R activation also blocks a Ca 2+ -activated potassium conductance, inhibits PLA2 and release of arachidonic acid, which may explain why H 1 R and H 2 R have opposite physiological responses in many tissues [9,10].

Histamine H 3 Receptor (H 3 R)
Histamine H 3 receptor (H 3 R) is widely distributed in the central nervous system, while low expressed in peripheral tissues. In situ hybridization studies reveal high levels of H 3 R mRNA in the cortex, hippocampus and caudate nucleus, followed by the anterior olfactory nucleus, amygdala, bed nucleus of stria terminalis, cerebellum and thalamus. The expression of H 3 R mRNA is low in habenula, zona incerta, globus pallidus, SN and substantia innominate etc. [28,29]. As a presynaptic autoreceptor on histaminergic neurons, the H 3 R mediates feedback inhibition of the release and synthesis of histamine. The H 3 R also distributes on the presynaptic membrane of non-histaminergic neurons and regulates the release of other neurotransmitters, such as dopamine, glutamate, GABA and acetylcholine. In addition, H 3 R acts as postsynaptic modulatory receptors in the striatum and cortex etc. [30]. The H 3 R (326-445 amino-acids) is located on chromosome 20q13.33. Due to the different connection between exons and introns, the coding region of the H 3 R gene can be composed of 3 exons (3965 bp) and 2 introns (2627 bp), or 4 exons (2418 bp) and 3 introns (2867 bp). The H 3 R is coupled to Gi/o proteins and plays an important role in the transduction process of downstream signaling pathways. The activation of H 3 R inhibits the adenylyl cyclase, decreasing the production of cAMP from adenosine triphosphate (ATP). H 3 R activation also leads to inhibition of high-voltage activated calcium channels, which reduces transmitter release in presynaptic terminals. In addition, H 3 R activates phosphorylation of the Akt/GSK-3 beta pathway, inwardly rectifying K+ channels, phospholipase C, phosphatidylinositide 3-kinases (PI3K) and mitogen-activated protein kinases (MAPK) [21,31,32].

Histamine H 4 Receptor (H 4 R)
Histamine H 4 receptor (H 4 R) is recently identified as a new member of the histamine receptor family, which is mainly expressed on the cells of the hematopoietic lineage and immune cells, such as mast cells, eosinophils and dendritic cells. H 4 R is also reported present in microglia with unconvincing evidence, whose function is still unclear. At present, the research on H 4 R mainly focuses on its role in the inflammatory process mediated by histamine. The H 4 R (390 amino-acids) is located on chromosome 18q11.2 and contains 3 exons and 2 introns. Moreover, H 4 R reveals~40% homology with H 3 R and acts through Gi/o proteins to reduce the accumulation of cAMP. In addition to cAMP, Ca 2+ is also the second messenger downstream of the H 4 R. Activation of H 4 R also increases the accumula-tion of Ca 2+ , activates the kinases (PI3K, MAPK, ERK) and transcription factor activator protein-1. In addition, H 4 R can bind to β-arrestin to activate MAPK pathways.

The Histaminergic System in Neuropsychiatric Disorders
The histaminergic system plays an important role in regulating various functions of the brain, such as sleep and wakefulness, learning and memory, feeding and energy balance. This review mainly introduces preclinical and clinical studies exploring the potential role of histaminergic system in neuropsychiatric disorders, including narcolepsy, schizophrenia, Alzheimer's disease, Tourette's syndrome and Parkinson's disease. Currently, several histamine receptor ligands are in clinical trials for the potential treatment of these neuropsychiatric disorders (Table 1).

Sleep Disorders
Histamine system is strongly suggested to play an essential role in modulating sleep and wake behavior via H 1 R and/or H 3 R. Histamine release is found to have a circadian rhythm, which is responsible for the modulation of sleep and wakefulness [33,34]. The histaminergic TMN neurons fire only during wakefulness and their activities are related to a high level of vigilance. In contrast, they cease firing and then remain quiescent during slow-wave sleep (SWS) and rapid eye movement sleep (REM) [16]. Additionally, the expression of immediate-early gene c-fos (a maker of neuronal activation) in histaminergic TMN neurons is higher during periods of wakefulness [23,35]. These results demonstrate that histaminergic neurons are wake-active and may play a crucial role in regulating wakefulness and wake-related behaviors. To elucidate the functions of histamine system on sleep-wakefulness, the genetically knockout mice are generated and has boosted research on histamine powerfully [36][37][38][39]. Compared to wild-type mice, HDC −/− mice exhibit a fragmented sleep-wake architecture with shortened episode duration and increased frequency of episodes in wakefulness and SWS, an increased REM sleep episodes mainly during the light phase and no major change in the daily amount of wakefulness or SWS [40]. duration of SWS and fewer transitions between SWS and wakefulness [41]. H 1 R is also expressed in astrocytes and astrocytic H 1 R regulates circadian rhythms and quality of wakefulness, but not the quantity and quality of sleep [25]. Interestingly, Hrh3 −/− mice show signs of increased histamine transmission and vigilance, while they exhibit deficient wakefulness and sleep fragmentation, which is most likely due to the decreased activity of histaminergic neurons and desensitization of postsynaptic histaminergic receptors [42]. Furthermore, numerous pharmacological interventions have been reported with similar conclusions [43][44][45]. At present, research into the neural circuitry of sleep and wakefulness has made remarkable progress. The VLPO of the hypothalamus is essential for sleep regulation and anatomical studies have shown that the VLPO and TMN are connected. The release of histamine from TMN neurons by using photostimulation disinhibits the wakeactive TMN neurons and indirectly suppresses sleep-active VLPO neurons through the activation of the GABAergic interneuron [46]. A recent study found that the preoptic area GABAergic neurons projecting to the TMN are both sleep active and sleep promoting by using a lentivirus for retrograde labelling and optogenetic manipulation [47]. In addition, the orexin/hypocretin (hypocretin neuropeptide precursor, HCRT) neurons are one important input to innervate and excite the TMN neurons during wakefulness [48,49]. Infusion of orexin A produces a significant increase in wakefulness, which dependeds on the activation of histaminergic neurotransmission mediated by H 1 R [50]. On the other hand, histamine also plays a regulatory role on the developing HCRT system via H 1 R [51]. It has been suggested that activity of TMN histaminergic neurons is important for enhancing arousal under certain conditions, such as exposure to a novel environment. Given the correlation between TMN histaminergic neurons excitability and behavioral arousal, Fujita et al. found that the tonic firing of histaminergic neurons is necessary for the maintenance of arousal during wakefulness, and their silencing is sufficient to impair arousal and induce SWS rapidly and selectively [52,53]. Additionally, some histamine neurons have the capacity to express the glutamic acid decarboxylase-67 (GAD67, GABA-synthesizing enzyme) and the vesicular GABA transporter (Vgat) gene [12,54]. Abdurakhmanova et al. show nice double-label in situ hybridization of HDC, Gad67 and Vgat mRNAs in the TMN and find that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states [55]. Selective deletion of Vgat gene expression from histaminergic TMN neurons increased wake during the night and locomotion [12]. A recent single-cell RNA sequencing (scRNA-seq) study found that TMN histaminergic neurons co-express very low Slc32a1 (encoding the vesicular GABA transporter) and exhibit a degree of transcriptional heterogeneity, a finding that adds further complexity to the heterogenous functions of these neurons [56]. Given the heterogeneity of TMN histaminergic neurons, it could be that the subset of histamine/GABA neurons these go into the cortex/striatum have substantial influence via volume transmission and can allow GABA release, and yet other populations (projecting to the VLPO) do not co-express GABA [52]. Further, the TMN histaminergic neurons innervate various downstream regions to regulate sleep-wakefulness, such as the cholinergic neurons in the basal forebrain (BF) or pedunculopontine and laterodorsal tegmentum, the serotonergic neurons in the dorsal raphe nucleus (DR), the dopaminergic neurons in the ventral tegmental area (VTA) or the noradrenergic neurons in the locus coeruleus (LC) (Figure 1) [23,57,58].
Narcolepsy is a disabling and chronic neurological disorder primarily characterized by irresistible sleep episodes and cataplexy [59]. Given histaminergic system comprises a major component of the arousal system and regulates sleep-wake cycle, its effect on narcolepsy has been extensively studied. Several studies have confirmed reduced cerebrospinal fluid (CSF) histamine levels in human narcolepsy especially in hypocretin-deficient narcolepsy [60][61][62], while a recent study reported that narcoleptic children with hypocretin deficiency had a higher CSF histamine level together with a lower t-MH level leading to a decreased histamine turnover and an impairment of histaminergic neurotransmission [63]. In addition, the number of histaminergic TMN neurons increased in patients with narcolepsy compared with the control group [64,65]. However, Robert et al. found that there were no significant differences between narcoleptic patients and control subjects in CSF histamine or t-MH levels [66,67]. Taken together, these above observations indicate the histaminergic system changes in the brain of narcoleptic patients, but further research is needed, especially the role of histaminergic system in different phenotypes of narcolepsy. The H 3 R antagonist/inverse agonist pitolisant (formerly known as BF2.649; tiprolisant) has been approved in the EU for the treatment of narcolepsy with or without cataplexy in adult patients and in the USA for the treatment of excessive daytime sleepiness in adult patients with narcolepsy [68]. Additionally, clinical studies have confirmed the long-term safety and therapeutic effect of pitolisant on daytime sleepiness, cataplexy, hallucinations and sleep paralysis repeatedly [69,70] (Table 1). Further, pitolisant is generally well tolerated and the severity of most adverse events are mild or moderate. Thus, based on the above findings, pitolisant could constitute an alternative treatment for patients with narcolepsy [68]. In summary, the TMN histaminergic neurons itself or through the innervation of other nervous systems participates in regulating the development of narcolepsy, and it is a potential target worth exploring for narcolepsy treatment. More importantly, the detailed mechanisms still need to be answered. colepsy has been extensively studied. Several studies have confirmed reduced cerebrospinal fluid (CSF) histamine levels in human narcolepsy especially in hypocretin-deficient narcolepsy [60][61][62], while a recent study reported that narcoleptic children with hypocretin deficiency had a higher CSF histamine level together with a lower t-MH level leading to a decreased histamine turnover and an impairment of histaminergic neurotransmission [63]. In addition, the number of histaminergic TMN neurons increased in patients with narcolepsy compared with the control group [64,65]. However, Robert et al. found that there were no significant differences between narcoleptic patients and control subjects in CSF histamine or t-MH levels [66,67]. Taken together, these above observations indicate the histaminergic system changes in the brain of narcoleptic patients, but further research is needed, especially the role of histaminergic system in different phenotypes of narcolepsy. The H3R antagonist/inverse agonist pitolisant (formerly known as BF2.649; tiprolisant) has been approved in the EU for the treatment of narcolepsy with or without cataplexy in adult patients and in the USA for the treatment of excessive daytime sleepiness in adult patients with narcolepsy [68]. Additionally, clinical studies have confirmed the long-term safety and therapeutic effect of pitolisant on daytime sleepiness, cataplexy, hallucinations and sleep paralysis repeatedly [69,70] (Table 1). Further, pitolisant is generally well tolerated and the severity of most adverse events are mild or moderate. Thus, based on the above findings, pitolisant could constitute an alternative treatment for patients with narcolepsy [68]. In summary, the TMN histaminergic neurons itself or through the innervation of other nervous systems participates in regulating the development of narcolepsy, and it is a potential target worth exploring for narcolepsy treatment. More importantly, the detailed mechanisms still need to be answered.

Schizophrenia
Schizophrenia is a common and severe psychiatric syndrome characterized by positive symptoms (e.g., delusions, hallucinations and paranoia), negative symptoms (e.g., alogia, social withdrawal, flattened affect and anhedonia) and cognitive deficits (impaired executive function, working memory and processing speed). Schizophrenia affects approximately 1% of the world population and causes considerable distress to the individual and society [71][72][73]. In recent years the role of histamine or its receptor as a pathophysiological contributor to a range of neuropsychiatric disorders, such as schizophrenia, has attracted the attention of researchers. Post-mortem studies have shown that the mean level of t-MH was elevated in the CSF of schizophrenia patients, suggesting increased

Schizophrenia
Schizophrenia is a common and severe psychiatric syndrome characterized by positive symptoms (e.g., delusions, hallucinations and paranoia), negative symptoms (e.g., alogia, social withdrawal, flattened affect and anhedonia) and cognitive deficits (impaired executive function, working memory and processing speed). Schizophrenia affects approximately 1% of the world population and causes considerable distress to the individual and society [71][72][73]. In recent years the role of histamine or its receptor as a pathophysiological contributor to a range of neuropsychiatric disorders, such as schizophrenia, has attracted the attention of researchers. Post-mortem studies have shown that the mean level of t-MH was elevated in the CSF of schizophrenia patients, suggesting increased central histaminergic activity in these patients [74]. In the dorsolateral prefrontal cortex, the average H 3 R expression of the schizophrenia patients, especially the ones treated with atypical antipsychotics, was significantly higher than those of the controls [75]. However, the human positron emission tomography (PET) study showed lower H 1 R binding in the frontal cortex, prefrontal cortex and cingulate cortex of schizophrenia people [76]. Indeed, some second-generation antipsychotics, including clozapine and olanzapine, have potent antagonistic effects on H 1 R. However, it remains incompletely understood that the ability of antipsychotics to block H 1 R is responsible for the therapeutic effects or the side effects of these compounds. Accordingly, the relationships between H 1 R occupancy and the main and side effects of atypical antipsychotics in patients should be elucidated in future [77]. Clinical trials have suggested the important influence of histamine receptors on schizophrenia patients, though the data are mixed. Since randomized clinical trial in 1990 of a positive therapeutic effect of the H 2 R antagonist famotidine on the negative symptoms in schizophrenia, the open-label study also indicated the effective role of the H 2 R antagonist ranitidine in negative symptoms [78,79]. Moreover, in a placebo-controlled, randomized clinical trial, famotidine has been observed to be beneficial to both the positive and negative symptoms in treatment-resistant schizophrenia, implying that H 2 R antagonism may provide a new alternative for the treatment of schizophrenia. Even though the preclinical studies in pharmacological models of schizophrenia have shown the protective effects of H 3 R inverse agonists, such as ABT-239, pitolisant, GSK207040, on the locomotor hyperactivity, the cognitive and sensory gating deficits, the clinical results of H 3 R inverse agonists in schizophrenia were disappointing unfortunately [80][81][82]. It has been reported that the H 3 R inverse agonists MK0249, ABT-288 and GSK239512, were not superior to placebo in the treatment of cognitive impairment in schizophrenia patients (Table 1). Further, the antipsychotics are widely used in the treatment of schizophrenia and one of the common adverse effects is weight gain, which is associated with increased risk of obesity in patients with schizophrenia. Betahistine, a weak partial H 1 R agonist and H 3 R antagonist, seem to reduce weight gain caused by antipsychotic drugs [83,84].
Our previous study indicates that H 1 R plays a cell-type-specific role in the brain [85,86]. Accordingly, we hypothesize that the cell-type specific H 1 R may be involved in the pathogenesis of schizophrenia. In our recent study, we generate the mice with a targeted deletion of H 1 R in different types of neurons, including glutamatergic neurons (CaMKIIα-Cre;Hrh1 fl/fl ), dopaminergic neurons (DAT-Cre;Hrh1 fl/fl ) or cholinergic neurons (ChAT-Cre;Hrh1 fl/fl ) by using the Cre-LoxP system and find that ChAT-Cre;Hrh1 fl/fl mice, instead of CaMKIIα-Cre;Hrh1 fl/fl or DAT-Cre;Hrh1 fl/fl mice, exhibit the behavioral deficits related to negative symptoms of schizophrenia. Then we confirm that the H 1 R expression in cholinergic neurons of basal forebrain (BF) is significantly decreased in patients with schizophrenia having negative symptoms. Finally, we verify that H 1 R in BF cholinergic neurons plays a key role in the pathogenesis of behavioral deficits in ChAT-Cre;Hrh1 fl/fl mice and identify the underlying circuit mechanism by selective re-expressing H 1 R in BF cholinergic neurons and activating/inhibiting the BF cholinergic neurons with chemogenetic methods (Figure 2) [87]. Our results suggest cell-type and BF region specific depletion of H 1 R functionality is responsible for the pathogenesis of negative symptoms of schizophrenia, which may be useful for the development of new drugs specifically aimed at patients expressing predominantly negative symptoms. Our study suggests that the complex results of previous postmortem sample studies and clinical trials may be due to the lack of selective interventions for brain regions and cell types. Clinical therapy for schizophrenia would benefit from the development of effective drug carrier for histamine receptor-targeted drug specifically delivered to brain regions or cell types.

Alzheimer's Disease (AD)
Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease and is marked by progressive memory loss, language impairment, behavioral changes and loss

Alzheimer's Disease (AD)
Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease and is marked by progressive memory loss, language impairment, behavioral changes and loss of functional abilities. AD is the most common cause for dementia and is characterized by the neurodegeneration, the loss of synapses, extracellular amyloid β (Aβ) peptidecontaining neuritic plaques and intracellular tau-positive neurofibrillary tangles in the most selected regions of the brain [88][89][90]. The role of histaminergic system in AD has remained conflicting. In 1989, Mazurkiewicz-Kwilecki and colleagues observed that the histamine levels in the frontal, temporal and occipital cortices and the caudate nucleus of postmortem AD samples were statistically significant decreased by using the double isotope technique [91], whereas Cacabelos and colleagues reported that the histamine levels in numerous regions except for the corpus callosum and globus pallidus, such as temporal cortex, hippocampus, putamen, caudate nucleus, thalamus and hypothalamus, were significantly higher in AD patients than controls by using the high-performance liquid chromatography (HPLC) with fluorometric detection [92]. Considering the limitations of past technology, Panula et al. used a very sensitive HPLC method in 1998, and found that the histamine content was significantly reduced in the hypothalamus, hippocampus and temporal cortex and showed no obvious change in other cortical areas, putamen and SN of AD samples [93]. Furthermore, subsequent studies confirmed that the total number of TMN neurons was significantly (57%) lost in AD patients, while in contrast there was no significant (24%) difference of total HDC mRNA expression in the entire TMN between AD patients and controls, suggesting compensatory processes [94,95]. It should be noted that H 3 R-and HNMT-mRNA expression in the prefrontal cortex increased only in female AD patients [94]. Accordingly, these discrepant findings may be attributable to complex factors, such as gender, age, postmortem delay (PMD), post mortem storage times and temperatures. Further, the amount of H 1 R binding assessed by positron emission tomography was significantly reduced in the frontal and temporal areas of AD patients compared to controls, revealing a disruption of the histaminergic neurotransmission in AD pathology [96].
There is a vast literature to unravel the essential role of histaminergic system in several aspect of fear and recognition memory acquisition, consolidation and retrieval, whose impairment is the first and most prominent symptom of AD [97,98]. The knockout mice are applied to explore the influence of the histaminergic system on cognition and the behavioral results of most knockout mice indicate signs of impaired learning and memory. Both Hrh1 −/− and Hrh2 −/− mice show impaired object recognition and spatial learning and hippocampal long-term potentiation (LTP), but improved acquisition of auditory and contextual freezing [99]. Hrh1 −/− mice also exhibit impairments of spatial reference and working memory in a reward-driven eight-arm radial maze task, temporal object memory and long-term motor memory [100][101][102]. In contrast to Hrh1 −/− mice that show unchanged performance in the passive avoidance test, Hrh2 −/− mice, compared to wild type mice, take more time to enter the dark compartment associated with electric shock [103,104]. Pharmacologic experiments also demonstrate that H 1 R antagonist impairs object recognition memory, spatial cognition in eight-arm radial maze and inhibitory avoidance memory retrieval [105,106] and H 2 R antagonist impairs object recognition memory and inhibitory avoidance memory [105]. However, contradictory results are also reported (e.g., intraventricular infusion of the H 1 R antagonist chlorpheniramine improves the performance in Morris water maze) [107]. Together, the above studies indicate that H 1 R or H 2 R has important impacts on the learning and memory implying that histaminergic system may be involved in the regulation of cognitive dysfunction in AD. Since HDC and H 3 R have unspecific effects on the production and release of histamine or several other neurotransmitters, HDC −/− and Hrh3 −/− mice exhibit more complex behavior changes. Similar to Hrh1 −/− and Hrh2 −/− mice, HDC −/− mice have improved auditory and contextual freezing, but they show no difference with wild type mice in novel object recognition test and perform better in the hidden platform water maze test [108][109][110][111][112]. H 3 R-deficiency do not seem to affect memory in object recognition and passive avoidance test, while the deficiency is associated with improved spatial learning and memory in the Barnes maze [39,113]. H 3 R antagonists show improved cognition in eight-arm radial maze task, water maze, Y-maze and so on [114][115][116]. In addition, a similar procognitive effect is observed when the APPTg2576 AD transgenic mice administered with H 3 R antagonist ciproxifan could alleviate the discrimination deficits in the object recognition test [117]. On the basis of the preclinical findings, a series of clinical trials on H 3 R antagonists for the treatment of AD have been carried out. In a double-blind, randomized, placebo controlled, parallel group study with a small group of patients (n = 8), over 4 weeks treatment of GSK239512 (a potent and selective H 3 R antagonist) displays a satisfactory level of tolerability and improved cognitive function in AD patients with mild to moderate symptoms [118]. In a subsequent randomized, doubleblind, placebo-controlled, 16-week study using a larger population, GSK239512 is used as a monotherapy in subjects with mild-to-moderate AD and improved episodic memory, but not executive function/working memory or other domains of cognition [119]. A randomized study of H 3 R antagonist ABT-288 to evaluate its efficacy and safety in subjects with mild-to-moderate AD is prematurely terminated, because ABT-288 dose groups do not significantly differ from placebo group, while the active comparator donepezil demonstrates statistically significant improvement, suggesting ABT-288 shows no efficacy in the symptomatic treatment of AD [120]. Another H 3 R inverse agonist MK0249 obtains similar results that administration of MK0249 over 4 weeks has no effect on cognitive function in mild to moderate AD patients [121] (Table 1). Even though these clinical trials fail to demonstrate unequivocal cognitive improvements, the first H 3 R antagonist pitolisant has received market approval from the European Medicines Agency for the treatment of narcolepsy. Thus, the procognitive activity of pitolisant may also expand therapeutic applications in AD.

Tourette's Syndrome (TS)
Tourette's syndrome (TS) is a developmental neuropsychiatric disorder characterized by multiple motor and vocal tics, present in childhood and lasting more than one year. According to the DSM-5 definition, tics are "sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations, generally preceded by urge" [122,123]. There have been many investigations into the relationship between the neuronal histaminergic system dysregulation and TS over the years. In 2010, Ercan-Sencicek and colleagues identified a nonsense mutation (W317X) in the HDC gene encoding L-histidine decarboxylase by an analysis of linkage in a two-generation family pedigree with an extremely high frequency of TS and represented that histamine dysregulation was related to TS for the first time [124]. Subsequently, Fernandez and Karagiannidis et al. studied variation across HDC for association with TS beyond this single family in succession and further supported the histaminergic hypothesis in TS etiology [125,126]. These genetic findings strongly implicate a causal relationship between the HDC mutations and TS and suggested a role for histaminergic system in the mechanism and modulation of TS. Accordingly, a number of studies have examined the HDC −/− mice in a variety of contexts especially the TS and related conditions. At baseline, HDC −/− mice exhibit no tic-like movements, elevated rearing or evident spontaneous motor stereotypies. However, HDC −/− mice show markedly increased motor locomotion and stereotypies after the acute administration with psychostimulant D-amphetamine when compared to wild type mice, suggesting that HDC deficiency can potentiate tics and tic-like stereotypies. Moreover, the stereotypies in HDC −/− mice could be mitigated by pretreatment with an efficacious treatment for tics, the D 2 R antagonist haloperidol. Another kind of behavioral defect of sensorimotor gating, which is reflected in a deficit in prepulse inhibition can be measured in TS patients carrying the HDC W317X mutation and the HDC −/− mice, which provided an additional behavioral parallel between TS patients and the HDC −/− mouse model. The pathophysiological mechanisms in the HDC −/− mouse model may be that reduced histamine production result in dysregulation of dopaminergic modulation of the basal ganglia and produces TS phenomenology [127]. Further, the centrality of striatal regulation by histaminergic TMN neurons is reported to be responsible for the production of pathological grooming and the H 3 R expression in the striatum of HDC −/− mice is markedly up-regulated, suggesting the H 3 R in the striatum is a contributor to the pathology and emerges as a novel treatment of tic disorders [128,129]. It has been reported that a male patient with tics and narcolepsy is treated with H 3 R antagonist/inverse agonist pitolisant and his daytime sleepiness decreased dramatically, whereas tic scores remain constant. Additionally, a two-part, randomized, multi-center, blinded study of H 3 R antagonist AZD5213 in adolescents with TS is conducted (Table 1). Compared to placebo group, the subjects exhibit no statistically difference when treated with the lower dose of drug and more severe tic symptoms when treated with the higher dose of drug. This worsening of tics may be interpreted as confirming the relevance of the receptor to pathophysiology of TS; however, the details need further investigations. Thus, more work is awaited to confirm the histaminergic hypothesis in TS to provide new strategies for disease treatment and prevention.

Parkinson's Disease (PD)
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms (i.e., resting tremor, rigidity, bradykinesia and postural instability) and non-motor symptoms (i.e., dementia, hyposmia and gastrointestinal alterations). PD is commonly accompanied by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), the major cause of Parkinsonian motor symptoms viz, and widespread presence of α-synuclein aggregations in the form of Lewy bodies (LBs) or Lewy neurites (LNs) [130,131]. Conflicting findings about the role of the neuronal histaminergic system in PD have been reported. Post mortem brain tissues of patients with PD show a strong accumulation of LBs and LNs in the TMN, indicating that TMN is severely damaged in the course of PD [132]. In spite of the abnormal accumulation in the TMN, no significant difference of HDC mRNA levels and number of histaminergic neurons are observed in TMN between PD patients and controls [133,134]. However, Rinne and colleagues found that although t-MH concentrations were unchanged in the putamen and temporal cortex, the local histamine levels of patients with PD significantly were increased in the SN (201%), putamen (159%) and globus pallidus (234%), who are responsible for motor behavior and functional changes in PD [135]. This is in line with the reports that in brains with PD the density of histaminergic fibers in the SN is increased, the morphology of histaminergic fibers is thinner than that of the control group and the varicosities are enlarged [136]. Furthermore, in the SN of PD patients the H 3 R mRNA expression is significantly reduced and HNMT mRNA expression is increased, and the level of HNMT mRNA correlate with PD disease duration negatively [137]. Together, the above observations imply although histamine production in the TMN does not alter significantly in PD, the local changes in the areas innervated by histaminergic neurons may contribute to PD pathology. It's noteworthy that local histamine changes in the areas, especially the SN, may be a rationale for potential therapeutic strategies.
In addition to post-mortem sample research, animal models and pharmacological research are used to study the pathogenesis of PD. The injection of α-FMH could decrease the rotation behavior induced by apomorphine and prevented the loss of Tyrosine hydroxylase (a marker for dopaminergic neurons) expressing cells in the 6-hydroxydopamine (6-OHDA)-lesioned rat, which is a classic PD model [138]. Moreover, HDC, H 1 R/H 2 R antagonists, and H 3 R agonist reduce the apomorphine-induced turning behavior in the 6-OHDA-lesioned rat [139]. H 2 R antagonist ranitidine and famotidine reduce dyskinesia induced by levodopa in rat models of PD [140,141]. Further, the histamine level is significantly increased and apomorphine-induced behavioral response is mainly alleviated by H 3 R antagonist thioperamide in 6-OHDA-lesioned rats [142]. Thioperamide also could rescue the memory impairment in the mouse model of PD [143]. The above findings imply that the histaminergic system acts as a modulating role in rats lesioned to model PD and may provide new drug therapies for PD. The clinical study show that H 2 R antagonist famotidine eases bradyphrenia and improve motor function in patients with PD [144]. In a single-blind trial of PD patients with excessive daytime sleepiness, the H 3 R antagonist pitolisant alleviates excessive sleepiness, but the motor performance is not significantly affected [145]. Nevertheless, these such compounds increasing local release of histamine in specific brain regions may be promising and provide therapeutic insights for PD treatment, which needs further exploration.

Concluding Remarks and Future Prospects
There is plethora of evidence implicating histaminergic system to play an essential role in the regulation of neuropsychiatric disorders. However, many challenges are still existing that need large amount of the future research: (1) to identify the precise and detailed mechanisms by which histaminergic system acts to regulate the neuropsychiatric disorders, (2) to elucidate the brain region-and cell-type specific role of histamine receptors and (3) to create selective and specific histamine receptors ligands that can be used to treat neuropsychiatric disorders. It is promising that further studies shed light on mechanism and pathology of neuropsychiatric disorders by using cutting-edge technology, such as chemo-genetic and optogenetic approaches, and facilitate the development of new drugs targeting the histaminergic system for the treatment of neuropsychiatric disorders.

Conflicts of Interest:
The authors declare no conflict of interest.