Baronio et al. Annals of General Psychiatry 2014, 13:34 http://www.annals-general-psychiatry.com/content/13/1/34 REVIEW Open Access Histaminergic system in brain disorders: lessons from the translational approach and future perspectives Diego Baronio1,2,3*, Taylor Gonchoroski1,3, Kamila Castro1,2,3, Geancarlo Zanatta1,3, Carmem Gottfried1,3 and Rudimar Riesgo1,2,3,4 Abstract Histamine and its receptors were first described as part of immune and gastrointestinal systems, but their presence in the central nervous system and importance in behavior are gaining more attention. The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action. The involvement of the histaminergic system in brain disorders, such as Alzheimer’s disease, schizophrenia, sleep disorders, drug dependence, and Parkinson’s disease, is largely studied. Data obtained from preclinical studies point antagonists of histamine receptors as promising alternatives to treat brain disorders. Thus, clinical trials are currently ongoing to assess the effects of these drugs on humans. This review summarizes the role of histaminergic system in brain disorders, as well as the effects of different histamine antagonists on animal models and humans. Keywords: Antagonist, Autism, Brain disorders, Histamine, Histaminergic system Introduction opioid, and galanin, regulate histamine release in specific Described for the first time in 1910 as a promoter of con- brain regions [4-6]. traction of smooth muscles and vasodilatation, histamine Histaminergic neurons are located in the tuberomamil- acts as a transmitter in the central nervous system (CNS) lary nucleus (TMN) of the hypothalamus, with widespread and modulates several other physiological processes, like projections innervating most brain areas. Postmortem gastrointestinal and circulatory functions, innate and studies indicate that the number of histaminergic neurons acquired immunity, cell proliferation and hematopoiesis. in humans is about 64,000 [7]. There are four histamine Today, its presence in the CNS and importance in behav- receptors, all part of the rhodopsin-like family of G pro- ior are largely studied [1,2]. tein-coupled receptors (GPCR). Through these receptors, Histamine synthesis and release are regulated by H3R, histamine regulates several basic body functions, such as an autoreceptor present in the somata and axon terminals wakefulness, feeding, and learning and memory [8-10]. of histaminergic neurons. Histamine is synthesized from L-histidine by histidine decarboxylase, and it is metabo- Histamine receptors N lized by diamine oxidase and histamine -methyltransfer- In 1966, Ash and Schild discovered the H1R while study- ase (HNMT) [3]. Other receptors, such as muscarinic, ing 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 * Correspondence: [email protected] part of the GPCR superfamily, and they all present consti- 1Translational Research Group in Autism Spectrum Disorders (GETTEA), tutive activity [12-15]. Ramiro Barcelos, 2350 - Santa Cecília, Porto Alegre RS 90035-903, Brazil The GPCR superfamily modulates several physiological 2Postgraduate Program in Child and Adolescent Health, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil processes and is divided into families and subfamilies, Full list of author information is available at the end of the article and single subtypes can present different isoforms. The © 2014 Baronio et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Baronio et al. Annals of General Psychiatry 2014, 13:34 Page 2 of 10 http://www.annals-general-psychiatry.com/content/13/1/34 discovery of constitutively active mutant receptors proved cyclase leading to cyclic adenosine monophosphate that these receptors could be activated without the pres- (cAMP) production, a second messenger that has dif- ence of an agonist [16]. Binding of a ligand to a receptor ferent roles in the cell [29]. The role of H2R in the CNS may initiate activity (agonist with positive intrinsic activ- is not fully understood, but basic research showed that ity) or prevent the effect of an agonist (antagonist with it is related to the processes of learning and memory, zero intrinsic activity). While the agonists stabilize the motor control, and thermoregulation [30,31]. In some receptor in active conformation, the inverse agonists areas of the brain, colocalization of H1R and H2R suggests stabilize the receptor in inactive conformation and thus synergistic interactions between these two receptors [32]. reduce the activity (negative intrinsic activity) [17]. Two In an animal model of multiple sclerosis, it was demon- isoforms of the H3R are highly constitutively active: the strated that both H1R and H2R are propathogenic, medi- wild type and an isoform with a deletion in the third ating immune deviation and blood brain barrier (BBB) intracellular loop [18]. disruption [33]. From the four histaminergic receptors, H1R is the Mainly found in the brain, H3R regulates food intake, main target of most of the approved drugs [19] and is memory, acetylcholine (ACh) release, and consolidation found in different tissues and cells, including the smooth of fear memories [34,35]. Activation of H3R inhibits cAMP muscle, brain, and lymphocytes [20,21]. This receptor is synthesis and activates MAP kinases and the AKT/GSK3β theonlymemberofthefamilyofhistaminereceptors, axis [36-38]. When activated, the receptor inhibits cell of which a co-crystal was obtained, by using the first- firing and decreases the release of histamine by histamin- generation antagonist doxepin (PDB ID 3RZE) [22]. ergic neurons, as well as inhibits secretion of norepineph- As for all members of this family, this receptor comprises rine, serotonin, and other neurotransmitters [13,39,40]. seven transmembrane helices (TMH), three intracellular Recently, several alterations were reported in mice lacking loops, and three extracellular loops. The binding pocket H3R. They presented enhanced histaminergic neurotrans- of H1R has a conserved hydrophobic nature, which mission, which led to changes in the mice phenotype, contributes to the low selectivity of doxepin and the indicating a possible metabolic disorder as a consequence. first-generation of H1R antagonists, and is associated to The sleep was also altered, in a condition similar to sleep an anion-binding region which has been related to the restriction in humans, which matches with obesity ten- binding of second-generation H1R antagonists. Such dency presented by these animals [41]. crystallographic structure can be used as a model in Almost 15 years ago, H4R was the last histamine recep- further development of new blockers as well as in the tor to be identified. It is mainly related with immune func- understanding of the activation-inactivation mechanisms tions, but its presence in the brain is known, as well as in of this receptor family at molecular level. The signal the bone marrow, peripheral blood, spleen, thymus, small transduction of H1R includes activation of phospholipase intestine, colon, heart, and lung [42-44]. It modulates dif- C, which promotes the inositol triphosphate-dependent ferent processes such as dendritic cells activity, interleukins release of Ca2+ from intracellular stores and diacylglyc- release, and likely regulation of BBB permeability [45-47]. erol-sensitive activation of protein kinase C [2,23]. In humans, the presence of H4R messenger RNA H1R is involved in the modulation of important (mRNA) was detected in the spinal cord, hippocampus, processes and mice lacking this receptor present different cerebral cortex, thalamus, and amygdala, with levels in impairments, for example, in spatial memory and in sleep- the spinal cord overcoming the levels found in the wake characteristics [24,25]. Injection of a H1R agonist in spleen and liver. The authors also verified the presence the median preoptic nucleus, a region involved in basal of the receptor in the dorsal root ganglia, which might thermoregulation, induces persistent hyperthermia [26]. indicate a nociceptive role for the receptor. In rats, the Other study with mutant mice lacking H1R suggested a cerebellum and hypothalamus presented the highest role for this receptor in somatic and visceral pain percep- amounts of H4R mRNA [48]. tions. These animals showed fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, Histaminergic system and brain disorders formalin, capsaicin, and abdominal constriction tests [27]. Alterations in the histaminergic system have been The pioneer study by Ash and Schild indicated, at that reported in several brain disorders and might have a time, the existence of at least two classes of histamine significant role in their pathophysiology [49-52]. Con- receptors,