Introduction
Described for the first time in 1910 as a promoter of contraction of smooth muscles and vasodilatation, histamine acts as a transmitter in the central nervous system (CNS) and modulates several other physiological processes, like gastrointestinal and circulatory functions, innate and acquired immunity, cell proliferation and hematopoiesis. Today, its presence in the CNS and importance in behavior are largely studied [
1],[
2].
Histamine synthesis and release are regulated by H3R, an autoreceptor present in the somata and axon terminals of histaminergic neurons. Histamine is synthesized from L-histidine by histidine decarboxylase, and it is metabolized by diamine oxidase and histamine
N-methyltransferase (HNMT) [
3]. Other receptors, such as muscarinic, opioid, and galanin, regulate histamine release in specific brain regions [
4]-[
6].
Histaminergic neurons are located in the tuberomamillary nucleus (TMN) of the hypothalamus, with widespread projections innervating most brain areas. Postmortem studies indicate that the number of histaminergic neurons in humans is about 64,000 [
7]. There are four histamine receptors, all part of the rhodopsin-like family of G protein-coupled receptors (GPCR). Through these receptors, histamine regulates several basic body functions, such as wakefulness, feeding, and learning and memory [
8]-[
10].
Histamine receptors
In 1966, Ash and Schild discovered the H1R while studying the effect of antihistamine drugs in the rat uterus and stomach [
11]. After that, three other receptors (H2R, H3R, and H4R) were identified. The four receptors are part of the GPCR superfamily, and they all present constitutive activity [
12]-[
15].
The GPCR superfamily modulates several physiological processes and is divided into families and subfamilies, and single subtypes can present different isoforms. The discovery of constitutively active mutant receptors proved that these receptors could be activated without the presence of an agonist [
16]. Binding of a ligand to a receptor may initiate activity (agonist with positive intrinsic activity) or prevent the effect of an agonist (antagonist with zero intrinsic activity). While the agonists stabilize the receptor in active conformation, the inverse agonists stabilize the receptor in inactive conformation and thus reduce the activity (negative intrinsic activity) [
17]. Two isoforms of the H3R are highly constitutively active: the wild type and an isoform with a deletion in the third intracellular loop [
18].
From the four histaminergic receptors, H1R is the main target of most of the approved drugs [
19] and is found in different tissues and cells, including the smooth muscle, brain, and lymphocytes [
20],[
21]. This receptor is the only member of the family of histamine receptors, of which a co-crystal was obtained, by using the first-generation antagonist doxepin (PDB ID 3RZE) [
22]. As for all members of this family, this receptor comprises seven transmembrane helices (TMH), three intracellular loops, and three extracellular loops. The binding pocket of H1R has a conserved hydrophobic nature, which contributes to the low selectivity of doxepin and the first-generation of H1R antagonists, and is associated to an anion-binding region which has been related to the binding of second-generation H1R antagonists. Such crystallographic structure can be used as a model in further development of new blockers as well as in the understanding of the activation-inactivation mechanisms of this receptor family at molecular level. The signal transduction of H1R includes activation of phospholipase C, which promotes the inositol triphosphate-dependent release of Ca
2+ from intracellular stores and diacylglycerol-sensitive activation of protein kinase C [
2],[
23].
H1R is involved in the modulation of important processes and mice lacking this receptor present different impairments, for example, in spatial memory and in sleep-wake characteristics [
24],[
25]. Injection of a H1R agonist in the median preoptic nucleus, a region involved in basal thermoregulation, induces persistent hyperthermia [
26]. Other study with mutant mice lacking H1R suggested a role for this receptor in somatic and visceral pain perceptions. These animals showed fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, formalin, capsaicin, and abdominal constriction tests [
27].
The pioneer study by Ash and Schild indicated, at that time, the existence of at least two classes of histamine receptors, since the antagonists utilized in that experiment did not stop gastric acid secretion [
11]. Later, compounds that blocked the gastric acid secretion in guinea pig, named H2R antagonists, were developed by Black and colleagues [
28]. Like H1R, H2R presents typical GPCR receptor characteristics. Its activation stimulates adenylyl cyclase leading to cyclic adenosine monophosphate (cAMP) production, a second messenger that has different roles in the cell [
29]. The role of H2R in the CNS is not fully understood, but basic research showed that it is related to the processes of learning and memory, motor control, and thermoregulation [
30],[
31]. In some areas of the brain, colocalization of H1R and H2R suggests synergistic interactions between these two receptors [
32]. In an animal model of multiple sclerosis, it was demonstrated that both H1R and H2R are propathogenic, mediating immune deviation and blood brain barrier (BBB) disruption [
33].
Mainly found in the brain, H3R regulates food intake, memory, acetylcholine (ACh) release, and consolidation of fear memories [
34],[
35]. Activation of H3R inhibits cAMP synthesis and activates MAP kinases and the AKT/GSK3β axis [
36]-[
38]. When activated, the receptor inhibits cell firing and decreases the release of histamine by histaminergic neurons, as well as inhibits secretion of norepinephrine, serotonin, and other neurotransmitters [
13],[
39],[
40]. Recently, several alterations were reported in mice lacking H3R. They presented enhanced histaminergic neurotransmission, which led to changes in the mice phenotype, indicating a possible metabolic disorder as a consequence. The sleep was also altered, in a condition similar to sleep restriction in humans, which matches with obesity tendency presented by these animals [
41].
Almost 15 years ago, H4R was the last histamine receptor to be identified. It is mainly related with immune functions, but its presence in the brain is known, as well as in the bone marrow, peripheral blood, spleen, thymus, small intestine, colon, heart, and lung [
42]-[
44]. It modulates different processes such as dendritic cells activity, interleukins release, and likely regulation of BBB permeability [
45]-[
47].
In humans, the presence of H4R messenger RNA (mRNA) was detected in the spinal cord, hippocampus, cerebral cortex, thalamus, and amygdala, with levels in the spinal cord overcoming the levels found in the spleen and liver. The authors also verified the presence of the receptor in the dorsal root ganglia, which might indicate a nociceptive role for the receptor. In rats, the cerebellum and hypothalamus presented the highest amounts of H4R mRNA [
48].
Perspectives
Over the last years, the role of histaminergic system has been studied in the pathophysiology of different brain disorders. Progress in this field of study has been made, making it possible to investigate different pharmacological approaches in order to treat or ameliorate symptoms. Autism, a neurodevelopmental disorder, affects 1 in 68 children in the US and has not a clear etiology or specific biomarkers [
105]. Literature presents scarce data about the histaminergic system in autism (Table
2), but the use of an H2R antagonist has been already proposed and tested in patients. Symptoms like irritability, hyperactivity, and atypical pattern of eye contact were attenuated after treatment with famotidine [
57],[
106].
Table 2
Studies involving autism and histamine
1972 | Neville et al. | 7 | - | Elevated plasma histidine and low skin histidase levels [ 107]. |
1979 | Kotsopoulos and Kutty | 1 | - | Patient with autism presented histidine blood levels seven times higher than the upper normal values [ 108]. |
1988 | Launay et al. | 22 | 22 | Histamine levels in urine and whole blood or plasma of patients with autism did not differ from age- and sex-matched controls [ 109]. |
1999 | Rossi et al. | 25 | - | Niaprazine (H1R antagonist) showed a positive effect on hyperkinesias, unstable attention, resistance to change and frustration, mild anxiety signs, hetero-aggressiveness, and sleep disorders [ 110]. |
2001 | Linday et al. | 9 | - | Behavioral improvement in children treated with Famotidine (H2R antagonist) [ 57]. |
2010 | Rosales-Reynoso et al. | 10 | 10 | Downregulation of H3R in patients with Fragile X syndrome, subjects that usually meet diagnostic criteria for autism [ 111]. |
2012 | Ming et al. | 48 | 53 | Reduced urinary levels of histidine and other amino acids [ 112]. |
2013 | Naushad et al. | 138 | 138 | When compared to normal controls, autistic children showed elevated levels of histidine (58 +/– 15 vs. 45 +/– 21 micromol/L) [ 113]. |
There is evidence that H3R is downregulated in Fragile X syndrome patients, a condition that is strongly associated with autism [
111]. In addition, animals exposed to phencyclidine (PCP) develop behavioral impairments, including low interest in social novelty, which is a feature present also in autism. In this experiment, animals exposed to PCP spent 3.5 less time investigating a novel subject than the control group. The administration of a H3R antagonist/inverse agonist, SAR110894, normalized this impairment [
72]. Recent data points to an involvement of the histaminergic system in the pathophysiology of Tourette’s syndrome, a condition common among patients with autism. A premature termination codon (W317X) in the histidine decarboxylase gene was detected in patients, implying that diminished histaminergic neurotransmission could be related to the outcomes of this syndrome [
114].
Since it is likely that the histaminergic system may play a role in SCH and Tourette’s syndrome, disorders that have substantial symptomatic overlap with autism, we think that further investigation should be made to characterize this system in autism. The animal model of autism based on prenatal exposure to valproic acid shows neuroanatomical, behavioral, and biochemical alterations that recapitulates the core characteristics of autism [
115], which makes it a reliable tool for studying a likely involvement of the histaminergic system in this disorder.
Initially described as part of immune and gastrointestinal systems, the presence of histamine and its four described receptors in the CNS have been related to normal and/or abnormal behavior. As a result, a growing amount of information regarding the relationship between histamine and brain is continuously arising from both experimental and clinical fields of research.
Based on preclinical data, different antagonists from histamine receptors have been considered promising therapies for brain disorders. On the other hand, more clinical studies are still required to verify practicability of these drugs. We believe that in-depth investigation involving the histaminergic system and its potential therapeutic targets in other disorders, such as autism, should be performed. Efforts in both preclinical and clinical research will lead to reaching clinically useful and safe treatments.
Competing interests
The authors declare that they have no competing interests.