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Home , Ciproxifan, GABAB receptor, H3 receptor antagonist, Histaminergic, Histamine H1 receptor, Histamine H2 receptor

14

HISTAMINE

JEAN-CHARLES SCHWARTZ JEAN-MICHEL ARRANG

In a certain way, systems have had a great, Data were comprehensively reviewed (4–7), and they are although indirect, historical importance in the development summarized only briefly here. of neuropsychopharmacology. Indeed, the discovery of both All known histaminergic perikarya constitute a continu- the neuroleptic agents and the tricyclic ous group of mainly magnocellular (about 2,000 in the 1950s was derived from the clinical study of behav- in the rat), located in the posterior and collec- ioral actions of ‘‘,’’ a class of antiallergic drugs tively named the tuberomammillary nucleus (Fig.14.1). It now designated H1- antagonists. can be subdivided into medial, ventral, and diffuse Nevertheless, the histaminergic neuronal system in the subgroups extending longitudinally from the caudal end of , although already understood by the mid-1970s, has the hypothalamus to the midportion of the third ventricle. remained largely unexploited in design. Thus, only the A similar organization was described in humans, except his- traditional brain-penetrating H1-receptor antagonists, used taminergic neurons are more numerous (approximately as over-the-counter sleeping pills, are known to interfere 64,000) and occupy a larger proportion of the hypothala- with histaminergic transmissions in the central nervous sys- mus (8). Besides their large size (25 to 35 ␮m), tuberomam- tem (CNS). This situation contrasts with the emergence, millary neurons are characterized by few thick primary den- in the 1990s, of detailed knowledge of the system that re- drites, with overlapping trees, displaying few axodendritic vealed that it shares many biological and functional proper- synaptic contacts. Another characteristic feature is the close ties with other aminergic systems overexploited in CNS contact of dendrites with glial elements in a way suggesting drug design. that they penetrate the ependyma and come in close contact and its receptors in the brain have been the with the cerebrospinal fluid, perhaps to secrete or receive subject of two comprehensive reviews (1,2). Therefore, to still unidentified messengers. Neurons expressing mRNAs limit the length of the present chapter, we have deliberately for decarboxylase (EC 4.1.1.22), the re- elected to summarize the detailed information that can be sponsible for the one-step histamine formation in the brain found in these reviews and have added only more recent (2), were found by in situ hybridization in the tuberomam- information and major references. millary nucleus, but not in any other brain area (9). Tubero- mammillary neurons possess the vesicular monoamine transporter 2 (10), which accounts for the histamine-releas- ORGANIZATION OF THE HISTAMINERGIC ing effect of reserpine (2). NEURONAL SYSTEM The histaminergic neurons are characterized by the pres- ence of an unusually large variety of markers for other neu- One decade after the first evidence by Garbarg et al. of an rotransmitter systems: decarboxylase, the ␥ ascending histaminergic pathway obtained by lesions of the -aminobutyric acid (GABA)–synthesizing enzyme; adeno- medial forebrain bundle (3), the exact localization of corre- sine deaminase, a cytoplasmic enzyme possibly involved in sponding perikarya in the posterior hypothalamus was re- adenosine inactivation; galanin, a co-localized with 5 6 7 vealed immunohistochemically, and the distribution, mor- all other monoamines; (Met )enkephalyl-Arg Phe , a prod- phology, and connections of histamine and histidine uct of the proenkephalin A ; and other neuropeptides decarboxylase-immunoreactive neurons were determined. such as substance P, thyroliberin, or brain natriuretic pep- tide. Tuberomammillary neurons also contain B, an enzyme responsible for deamination of tele- methylhistamine, a major histamine metabolite in brain. Jean-Charles Schwartz and Jean-Michel Arrang: Unite´ de Neurobiolo- gie et Pharmacologie Mole´culaire de l’INSERM, Centre Paul Broca, Paris, Finally, a subpopulation of histaminergic neurons is able to France. take up and decarboxylate exogenous 5-hydroxytryptophan, 180 Neuropsychopharmacology: The Fifth Generation of Progress

external layers. Other major areas of termination of these long ascending connections are the olfactory bulb, the hip- pocampus, the caudate , the nucleus accumbens, the globus pallidus, and the amygdaloid complex. Many hypothalamic nuclei exhibit a very dense innervation, for example, the suprachiasmatic, supraoptic, arcuate, and ven- tromedial nuclei. A Finally, a long descending histaminergic subsystem also arises from the tuberomammillary nucleus to project to var- ious mesencephalic and brainstem structures such as the cranial nerve nuclei (e.g., the trigeminal nerve nucleus), the central gray, the colliculi, the substantia nigra, the locus ceruleus, the mesopontine tegmentum, the dorsal raphe nu- cleus, the (sparse innervation), and the spinal cord. Several anterograde and retrograde tracing studies estab- lished the existence of afferent connections to the histamin- ergic perikarya, namely, from the infralimbic cortex, the septum-diagonal band complex, the preoptic region, the hypothalamus, and the hippocampal area (subiculum) (7, B 11). Sleep-active GABAergic neurons in the ventrolateral FIGURE 14.1. Localization of histaminergic perikarya (closed cir- preoptic nucleus provide a major input to the tuberomam- cles) in tuberomammillary nucleus and disposition of main hista- millary nucleus (12,13). Histaminergic neurons also receive minergic pathways (arrows) in rat brain. A: Frontal section of the very dense innervation originating from the lateral caudal hypothalamus. B: Sagittal section of the brain. AH, ante- rior hypothalamic area;Arc, arcuate nucleus;cc, corpus callosum; hypothalamus (14). Electrophysiologic studies provided evi- Cer, cerebellum;CG, central gray;CX, ;DR, dorsal dence of inhibitory and excitatory synaptic control of tuber- raphe nucleus;f, fornix;Hip, ;LS, lateral septum; omammillary activity by afferents from the diagonal MD, mediodorsal thalamus;MMn, medial mammillary nucleus median part;OB, olfactory bulb;Pn, pontine nuclei;Sol, nucleus band of Broca, the lateral preoptic area and the anterior of solitary tract;Sox, supraoptic decussation;sum, supramammil- lateral hypothalamic area (15). Projections from the brain- lary nucleus;TMdiff, tuberomammillary nucleus diffuse part; stem to the tuberomammillary nucleus have also been dem- TMVr, ventral tuberomamillary subgroup rostral part;VDB, nu- onstrated. Retrograde tracing studies combined with immu- cleus of vertical limb of diagonal band;VMH, ventromedial hypo- thalamic nucleus. nohistochemistry showed that inputs to the tuberomammillary nucleus originate mainly from the ven- trolateral and dorsomedial medulla oblongata and from the raphe nuclei, with a low innervation originating from the locus ceruleus, the ventral tegmental area, and the substantia a compound that they do not synthesize, however (5). Dis- nigra (16). covering the functions of such a high number of putative cotransmitters in the same neurons remains an exciting chal- lenge. MOLECULAR AND Like other monoaminergic neurons, histaminergic neu- LOCALIZATION OF rons constitute long and highly divergent systems projecting SUBTYPES in a diffuse manner to many cerebral areas (Fig.14.1). Im- munoreactive, mostly unmyelinated, varicose or nonvari- Three histamine receptor subtypes (H1,H2 and H3) have cose fibers are detected in almost all cerebral regions, partic- been defined by means of functional assays, followed by ularly limbic structures, and it was confirmed that design of selective and antagonists and, more re- individual neurons project to widely divergent areas. Ultra- cently, cloning of their (1). All three belong to the structural studies suggest that these fibers make few typical superfamily of receptors with seven transmembrane do- synaptic contacts (6). mains (TMs) and coupled to guanylnucleotide-sensitive G Fibers arising from the tuberomammillary nucleus con- proteins (Table 14.1). In addition, histamine affects the stitute two ascending pathways: one laterally, through the N-methyl-D-aspartate (NMDA) receptor (17, medial forebrain bundle, and the other periventricularly. 18). These two pathways combine in the diagonal band of Broca HistamineH Receptor to project, mainly in an ipsilateral fashion, to many telence- 1 phalic areas, for example, in all areas and layers of the cere- The H1 receptor was initially defined in functional assays bral cortex, the most abundant projections being to the (e.g., contraction) and in the design of po- Chapter 14: Histamine 181

TABLE 14.1. PROPERTIES OF THREE HISTAMINE RECEPTOR SUBTYPES

H1 H2 H3

Coding sequence 491 a.a. (bovine) 358 a.a. (rat) 445 a.a. (human)

488 a.a. (guinea pig) 359 a.a. (dog, human, H3L 445 a.a., H3S 415 a.a. 486 a.a. (rat) guinea pig) (guinea pig)

H3L 445 a.a., H3S 413 a.a. (rat) 3p25 5 20qTEL localization Highest brain Thalamus Striatum Striatum densities Cerebellum Cerebral cortex Frontal cortex Hippocampus Amydgala Substantia nigra No No Yes Affinity for Micromolar Micromolar Nanomolar histamine Characteristic 2-(3-Trifluoromethyl) (R)α-Methylhistamine agonists histamine Sopromidine Characteristic antagonists Radioligands [3H]Mepyramine [3H]Tiotidine [3H](R)α-Methylhistamine [125I]lodobolpyramine [125I]lodoamino- [125I]lodoproxyfan potentidine Second Inositol phosphates (+) cAMP (+) cAMP (–) messengers Arachidonic acid (+) Arachidonic acid (–) Inositol phosphates (–) cAMP (potentiation) Ca++ (+) Arachidonic acid (+) Ca++ (–)

tent antagonists, the so-called antihistamines (e.g., mepyra- to that of other receptors positively coupled to phospholi- mine), most of which display prominent sedative properties. pases A2 and C. between Biochemical and localization studies of the H1 receptor were the TMs of the H1 and those of the muscarinic receptors made feasible with the design of reversible and irreversible (approximately 45%) is higher than between those of H1 3 125 radiolabeled probes such as [ H] mepyramine, [ I]iodo- and H2 receptors (approximately 40%). H1-receptor antag- bolpyramine, and [125I]iodoazidophenpyramine (19,20). onists often display significant antimuscarinic activity but Various intracellular responses were found to be associ- only limited H2-receptor–antagonist properties. ated with H1-receptor stimulation: inositol phosphate re- A single gene seems to encode the guinea pig H1 receptor, fluxes, cyclic adenosine monophos- and mRNAs of similar size were detected in brain areas and םlease, increase in Ca2 phate (cAMP) or cyclic guanosine monophosphate peripheral tissues (22).The structure of the human gene was accumulation in whole cells and arachidonic acid release disclosed (23). Like other receptors of this superfamily, it (1). contains an intron in the 5′ flanking untranslated region, The deduced amino acid sequence of a bovine H1 recep- close to the translation initiation codon, but the translated tor was disclosed after expression cloning of a corresponding region is intronless. When stably expressed in transfected fibroblasts, the -םcDNA. The latter was based on the detection of a Ca2 מ dependent Cl influx into microinjected Xenopus oocytes. guinea pig H1 receptor was found to trigger a large variety After the transient expression of the cloned cDNA into of intracellular signals involving or not coupling to pertussis ם2 COS-7 cells, the identity of the protein as an H1 receptor toxin-sensitive G proteins (Gi or Go), namely, Ca tran- was confirmed by binding studies (21). sients, inositol phosphates, or arachidonate release (24). H1 Starting from the bovine sequence, the H1 receptor DNA receptor stimulation potentiates cAMP accumulation in- was also cloned in the guinea pig (22), a species in which duced by forskolin in the same transfected fibroblasts, a the pharmacology of the receptor is better established, as response that resembles the H1 potentiation of histamine well as from several other species including humans (1). H2- or adenosine A2-receptor–induced accumulation of Although marked species differences in H1-receptor phar- cAMP in brain slices. All these responses mediated by a macology had been reported (2), the sequence homology single H1 receptor were known to occur in distinct lines between the putative TMs of the proteins is high (90%). or brain slices, but they could have resulted from stimulation The ‘‘anatomy’’ of the H1 receptor, with a long third of isoreceptors. intracellular domain and a short C-terminal tail, is similar Constitutive activity of the recombinant human H1 re- 182 Neuropsychopharmacology: The Fifth Generation of Progress

ceptor consisting in an -independent increase in ino- pal pyramidal neurons, H2-receptor stimulation potentiates -con םactivated K-םsitol phosphates accumulation in COS-7 cells was evi- excitatory signals by decreasing a Ca2 denced. Several H1-receptor antagonists behaved as inverse ductance, presumably by cAMP production (26). H2-recep- agonists (i.e., reduced this constitutive activity), but the tor activation depolarizes thalamic relay neurons slightly and physiologic relevance of the process, such as in brain, was increases apparent membrane conductance markedly, re- not established (25). sponses caused by enhancement of the hyperpolarization- The H1 receptor mediates various excitatory responses activated cation current Ih (27). In addition to these short- -lasting effects, histamine also induces very long-lasting in םin brain (26). A reduction of a background leakage K current was implicated in these responses, in cortical, stria- creases in excitability in the CA1 region of the hippocampus tal, and lateral geniculate relay neurons (27,28). through activation of H2 receptors and the cAMP/cAMP- H1-receptor distribution in the guinea pig brain was es- dependent protein kinase signal transduction cascade. This 3 tablished autoradiographically using [ H]mepyramine or process is modulated by other receptors such as the H1 re- the more sensitive probe [125I]iodobolpyramine (20), and ceptor (35). the information was complemented by in situ hybridization The sole selective H2- known to enter of the mRNA (22). For instance, the high density of H1 the brain is , a compound used sometimes in receptors in the molecular layers of cerebellum and hippo- animal behavioral studies but not introduced in therapeutics campus seems to correspond to dendrites of Purkinje and (36). However, some tricyclic are known pyramidal cells, respectively, in which the mRNA is highly to block H2-receptor–linked potently and 125 expressed. H1 receptors are also abundant in guinea pig interact with [ I]iodoaminopotentidine binding in a com- thalamus, hypothalamic nuclei (e.g., ventromedial nuclei), plex manner (37). nucleus accumbens, amygdaloid nuclei, and frontal cortex Autoradiographic localization of the H2 receptor in but not in neostriatum (20), whereas they are more abun- guinea pig (20) and human brain (29) shows it distributed dant in the human neostriatum (29). The H1 receptor was heterogeneously. The H2 receptor is found in most areas visualized in the primate and human brain in vivo by posi- of the cerebral cortex, with the highest density in the superfi- tron emission tomography using [11C]mepyramine (30). cial layers, the piriform, and the occipital cortices, which Blockade of H1 receptors located in cerebral areas in- contain low H1-receptor density. The caudate putamen, the volved in wakefulness and cognition, and including those ventral striatal complex, and the amygdaloid nuclei (bed mediating excitation of thalamic relay neurons (31), neo- nucleus of the stria terminalis) are among the richest brain cortical pyramidal neurons (28) and ascending areas. In the hippocampal formation, the relative localiza- neurons (32,33), presumably accounts for the sedative prop- tions of the H2 receptor and its gene transcripts are similar erties of ‘‘antihistamines’’ of the first generation. to those observed for the H1 receptor: the gene transcripts are expressed in all pyramidal cells of the Ammon horn and in cells of the dentate gyrus (38), whereas the H2 HistamineH 2 Receptor receptor is expressed in the molecular layers of these areas, which contain the dendritic trees of the mRNA-containing The molecular properties of the H2 receptor remained neurons. The partial overlap with the H receptor may ac- largely unknown for a long time. Reversible labeling of the 1 3 count for their synergistic interaction in cAMP accumula- H2 receptor was achieved using [ H]tiotidine or, more relia- tion. bly, [125I]iodoaminopotentidine (2). By screening cDNA or genomic libraries with homolo- gous probes, the intronless gene encoding the H receptor 2 HistamineH Receptor was first identified in dogs (34) and, subsequently, in other 3 species including humans (1). The H2 receptor is organized The H3 receptor was initially detected as an autoreceptor like other receptors positively coupled to adenylyl cyclase: controlling histamine synthesis and release in brain. There- it displays a short third intracellular loop and a long C- after, it was shown to inhibit presynaptically the release of terminal cytoplasmic tail. other monoamines in brain and peripheral tissues as well Using transfected cell lines, positive linkage of the H2 as of neuropeptides from unmyelinated C fibers (39,40). receptor with adenylyl cyclase was confirmed, and unex- Reversible labeling of this receptor was first achieved pected inhibition of arachidonate release and stimulation using the highly selective agonist [3H](R)␣-methylhista- ␣ 3 ם2 of Ca transients was evidenced (1). Hence H2 receptor mine (2), then [ H]N -methylhistamine, a less selective ag- stimulation can trigger intracellular signals either opposite onist, was also proposed (19), as well as, more recently, 125 125 or similar to those evoked by H1 receptor stimulation. Paral- [ I] and [ I]iodoproxyfan, two antago- lel observations were made for a variety of biological re- nists (41). sponses mediated by the two receptors in peripheral tissues. The regulation of agonist binding by guanylnucleotides Helmut Haas and colleagues showed that, in hippocam- (39), and the sensitivity of several H3-receptor–mediated Chapter 14: Histamine 183

responses to pertussis toxin (42,43), suggested that the H3 Interaction with NMDA Receptors receptor was G / coupled, a suggestion confirmed i o Histamine potentiates NMDA-evoked currents in acutely by the cloning of the corresponding human (44) and rodent dissociated and cultured hippocampal and cortical neurons, (45) cDNAs. The H receptor gene contains two introns 3 an effect that could not be ascribed to activation of the in its coding sequence and several splice variants H3L and known histamine receptors (17,18), but rather of a novel H3S differing by a stretch of 30 amino acids in the third recognition site on NMDA receptors containing the sub- intracellular loop, were identified (45). The existence of units NR1A/NR2B (53). these variants may partly account for the apparent H3-recep- Histamine may play a role in modulating the functions of tor heterogeneity in binding or functional studies (46). NMDA receptors in vivo. It facilitates the NMDA-induced Significant differences in the pharmacology of the depolarization of projection neurons in cortical slices (54) human and rodent H3 receptor (47) could be assigned to and phase shifts the circadian clock by a direct potentiation differences in only two amino acid residues in the third TM of NMDA currents in the suprachiasmatic nucleus (55). (48). In various cell lines, stimulation of the H3 receptor, Histamine, presumably acting through NMDA receptors, like that of other Gi-protein–coupled receptors, inhibits facilitates the induction of long-term potentiation and adenylate cyclase (44) or (42) and activates causes long-lasting increases of excitability in the CA1 re- phospholipase A2 (48a). gion of rat hippocampal slices (35). On neurons, the H3 receptor mediates presynaptic inhi- The histamine-induced modulation of NMDA responses bitions of release of several , including his- is higher under slightly acidic conditions (56), which occur tamine itself (2,39), , , , during hypoxia or epileptiform activity. This may lead to glutamate, GABA, and tachykinins (40), presumably by in- enhancement of or histamine-mediated hibiting voltage-dependent calcium channels (39,43). neuronal death such as that observed in a rat model of Wer- Several H3-receptor antagonists, such as thioperamide nicke encephalopathy (57). and ciproxifan, potently enhance histamine release in vitro and in vivo (2,39,49).This response was originally attributed to blockade of the inhibitory effects of endogenous hista- HISTAMINERGIC NEURON ACTIVITY AND mine and was therefore used in many studies, such as behav- THEIR CONTROL ioral studies, to delineate the functions of histaminergic Electrophysiologic Properties neurons. However, these drugs were shown to act, in fact, as inverse agonists, and the native H3 receptor in brain dis- Cortically projecting histaminergic neurons share with other play high constitutive activity including in vivo (48a). aminergic neurons certain electrophysiologic properties evi- denced by extracellular recording. They fire spontaneously Autoradiography of the H3 receptor in rat (50,51) and monkey brain shows it highly concentrated in the neostria- slowly and regularly, and their action potentials are of long tum, the nucleus accumbens, the cingulate and infralimbic duration (26). Among the pacing events that may contribute cortices, the bed nucleus of the stria terminalis, and the to their spontaneous firing, tuberomammillary neurons ex- ,(current (58 םhibit a tetrodotoxin-sensitive persistent Na ם -substantia nigra pars lateralis. In contrast, its density is rela aCa2 current probably of the low-threshold type (59), ם -tively low in the hypothalamus (including the tuberomam and multiple high-voltage–activated Ca2 currents (43). In millary nucleus), which contains the highest density of hista- addition, they exhibit inward rectification attributed to an minergic axons (and perikarya), a finding indicating that Ih current that may increase whole-cell conductance and most H3 receptors are not . In agreement with may decrease the efficacy of synaptic inputs during periods this concept, intrastriatal kainate strongly decreases H3 of prolonged hyperpolarization , that is, when histaminergic binding sites in the forebrain (as well as in the substantia neurons fall silent (60). nigra, consistent with their presence in striatonigral neu- rons) (50,51). In the human brain, the high densities of H3 receptors found in the striatum and globus pallidus (29) Modulation of HistamineSynthesisand were lower in patients with Huntington disease, a finding Release In Vitro suggesting that the H3 receptor is also located on striatoni- The autoreceptor-regulated modulation of histamine syn- gral projection neurons of the direct and indirect pathways thesis in, and release from, brain neurons is well docu- (52). Consistent with the proposal that most H3 receptors mented (2). It was initially evidenced in brain slices or syn- are not autoreceptors, a strong expression of H3-receptor aptosomes after labeling the endogenous pool of histamine mRNAs was observed not only within the tuberomammil- using the [3H]histamine precursor. Exogenous histamine lary nucleus, but also in various regions of the rat (44) and decreases the release and formation of [3H]histamine in- guinea pig (45) brain, including the cerebral cortex, the duced by depolarization, and analysis of these responses led , and the thalamus. to the pharmacologic definition of H3 receptors. The auto- 184 Neuropsychopharmacology: The Fifth Generation of Progress

regulation was found in various brain regions known to active phase (2). In mouse cerebral cortex, striatum, and contain histamine nerve endings, a finding suggesting that hypothalamus, telemethylhistamine levels are doubled at the all terminals are endowed with H3 autoreceptors. end of the dark phase of the cycle as compared with the Regulation of histamine synthesis was also observed in beginning of the light phase (66). Histamine release from the posterior hypothalamus (39), and somatodendritic H3 the anterior hypothalamus of freely moving rats, evaluated autoreceptors inhibit the firing of tuberomammillary neu- by in vivo microdialysis, gradually increases in the second rons (26) by modulating high-voltage–activated calcium half of the light period and is maintained at a maximal level channels (43). during the active phase (67). Such state-related changes are Galanin, a putative cotransmitter of a subpopulation of also found in single-unit extracellular recordings performed histaminergic neurons, regulates histamine release only in in the ventrolateral posterior hypothalamus of freely moving regions known to contain efferents of this subpopulation, cats. Neurons with properties consistent with those of hista- that is, in hypothalamus and hippocampus but not in cere- minergic neurons exhibited a of their fir- bral cortex or striatum (61). In brain slices, galanin also ing rate, falling silent during deep slow-wave or paradoxical hyperpolarizes and decreases the firing rate of tuberomam- sleep (2). An important determinant of this circadian millary neurons (26). It is not known, however, whether rhythm of tuberomammillary histaminergic neuron activity these galanin receptors behave as ‘‘autoreceptors’’ modulat- is a GABAergic inhibitory pathway originating in the ven- ing galanin release from histaminergic nerve terminals, inas- trolateral preoptic area and activated during sleep (12,15). much as the tuberomammillary nucleus receives a strong A feeding-induced increase in the activity of histaminer- galaninergic innervation from the ventrolateral preoptic area gic neurons has also been shown by microdialysis performed (12,13). Other putative cotransmitters of histaminergic in the hypothalamus of conscious rats (68). Histaminergic neurons failed to affect [3H]histamine release from slices of neurons are a target for leptin in its control of feeding is rat cerebral cortex (62). However, GABAergic inhibitory unclear. An enhancement of histamine turnover was ob- postsynaptic potentials are mediated by GABAA receptors served after intracerebroventricular infusion of leptin (70). located on histaminergic neurons (63). To what extent these Changes in the and release of histamine ob- receptors play an autoinhibitory role is unclear. A subpopu- served in vivo after occlusion of the middle cerebral artery lation of histaminergic neurons contains GABA (5), but the in rats suggest that the histaminergic activity is also en- tuberomammillary nucleus also receives dense GABAergic hanced by cerebral (71). innervation (12,13,15). Whereas H1 and H2 receptors are apparently not in- 3 [ H]Histamine synthesis and release are inhibited in var- volved, inhibition mediated by the H3-autoreceptor consti- ious brain regions by stimulation of not only autoreceptors tutes a major regulatory mechanism for histaminergic neu- ␣ but also 2- receptors, M1-muscarinic receptors, ron activity under physiologic conditions. Administration ␬ and - receptors (2). Because these regulations are of selective H3 receptor agonists reduces histamine turnover also observed with synaptosomes (62), all these receptors (2) and release, as shown by microdialysis (72). In contrast, presumably represent true presynaptic . In H3-receptor antagonists enhance histamine turnover (2,49) contrast, histamine release is enhanced by stimulation of and release in vivo (73,74), a finding suggesting that auto- nicotinic receptors in rat hypothalamus (64) and by ␮-opi- receptors are tonically activated. oid receptors in mouse cerebral cortex (2). Agents inhibiting histamine release in vitro through stim- ␣ Some molecular mechanisms regulating neuronal hista- ulation of presynaptic 2-adrenergic or muscarinic hetero- mine dynamics remain unclear. N-methylation catalyzed by receptors reduce histamine release and turnover in vivo, but histamine N-methyltransferase is the major process respon- systemic administration of antagonists of these receptors sible for termination of histamine actions in the brain (2), does not enhance histamine turnover, a finding suggesting and genetic polymorphisms for the enzyme have been asso- that these heteroreceptors are not tonically activated under ciated with altered levels of its activity (65). No histamine basal conditions. transporter could be evidenced, and direct feedback inhibi- Activation of central nicotinic receptors inhibits hista- tion of by histamine has been ex- mine turnover (75). Several types of receptors cluded (2). are likely to modulate histamine neuron activity. 5-Hy- droxytryptamine (5-HT)1A–receptor agonists inhibit (76), Changes in Histaminergic Neuron whereas 5-HT2–receptor antagonists enhance (77), hista- mine turnover in various brain regions. Stimulation of D2 Activity In Vivo (but not D3) dopamine receptors by endogenous dopamine Both neurochemical and electrophysiologic studies indicate released by amphetamine increases histamine neuron activ- that the activity of histaminergic neurons is high during ity (77,78). arousal. In rat hypothalamus, histamine levels are low, Histamine turnover in the brain is rapidly reduced after whereas synthesis is high during the dark period, a finding administration of various sedative drugs such as , suggesting that neuronal activity is enhanced during the ⌬9-tetrahydrocannabinol, barbiturates, and benzodiaze- Chapter 14: Histamine 185 pines (2), presumably as a result of their interaction with in contrast, neurons releasing the neuropeptide orexin that GABA receptors present on nerve endings and on perikarya emanate from the lateral hypothalamus appear to exert op- of histaminergic neurons (63,79). posite actions because disruption of the orexin gene is associ- In contrast, stimulation of ␮-opioid receptors enhances ated with in dogs and knockout mice (14,82). histamine turnover in brain (2). NMDA receptors increase Other monoaminergic neurons participating in control of in vivo release of histamine from the anterior hypothalamus sleep and wakefulness states as well as GABA/galanin ven- (80). Activation of NMDA and non-NMDA receptors in trolateral preoptic neurons also receive inputs from orexin the diagonal band of Broca, the lateral preoptic area, and neurons, which are, themselves, likely influenced by photic the anterior hypothalamic area led to inhibition or enhance- signals from the suprachiasmatic nucleus. In turn, neurons ment of firing rates of tuberomammillary neurons (15). from the suprachiasmatic nucleus and the preoptic area seem to be influenced in a complex manner by histaminergic inputs (83,84). Hence a complex neuronal network in the PHYSIOLOGIC ROLES OF HISTAMINERGIC hypothalamus with reciprocal influences involving hista- NEURONS minergic neurons seems to control wakefulness. The major part played by the H1 receptor in these pro- In spite of many different suggestions mainly derived from cesses, confirmed in mutant mice lacking this receptor (85), the observations of responses to locally applied histamine, accounts for the sedating effects of the first generation of only a few physiologic roles of histaminergic neurons appear ‘‘antihistamines,’’ that is, antagonists that easily enter the relatively well documented. brain and are still ingredients of over-the-counter sleeping pills (86). It may also account for the sedative side effects of many antipsychotic or antidepressant drugs that are po- Arousal tent H1 antagonists. Our initial proposal in 1977 (81) that histaminergic neu- rons play a critical role in arousal has been confirmed by CognitiveFunctions data from a variety of experiments mainly performed by The idea that histaminergic neurons may improve cognitive Lin and Jouvet in cats (33) and Monti in rats (2). In agree- performance is consistent with projections of these neurons ment with this concept, ablation of these neurons and inhi- to brain areas such as the prefrontal and cingulate cortices or bition of histamine synthesis, release, or action by the H 1 hippocampus, their excitatory influences therein, and their receptor decrease wakefulness and increase deep slow-wave positive role in wakefulness. sleep; conversely, inhibition of histamine methylation or Ciproxifan, a potent and selective H -receptor antagonist facilitation of histamine release by H receptor blockade 3 3 (or ), which strongly enhances histamine increase arousal (49). turnover in brain, improved attentional performances in the The arousing effect of histamine may result from H 1 rat five-choice test under conditions similar to those of drugs and H -receptor–mediated depolarization of thalamic relay 2 enhancing cholinergic transmissions (49). Various H an- neurons that induces a shift of their activity from burst 3 tagonists facilitate various forms of learning. They improve firing (predominating in deep sleep during which they are short-term social memory in rats (87), reverse the scopolam- poorly responsive to sensory inputs) to single spike activity ine- or senescence-induced learning deficit in a passive (predominating in arousal during which sensory informa- avoidance test in mice (88), and facilitate retention in a tion is more faithfully relayed) (31). Arousal may also result footshock avoidance test in mice (89). from H -receptor–mediated excitation of neocortical pyra- 1 Generally, H agonists exert opposite effects, and the midal neurons by the same mechanism as in thalamus, that 3 effects of H -antagonists are reversed by H antagonists, a is, reduction of a background leakage potassium current 3 1 finding that suggests that these effects are attributable to (28). Finally, arousal may occur indirectly by H -recep- 1 enhanced histamine release. In contrast to the large body tor–mediated excitation of ascending cholinergic neurons of experiments indicating a ‘‘procognitive’’ role of tubero- within the nucleus basilis or mesopontine tegmentum (32, mammillary neurons, Huston and coworkers repeatedly 33), which also induces cortical activation. showed that excitotoxic lesions aimed at these neurons abla- All these cellular actions of histamine, together with ob- tion result in improvement of learning in a variety of tests servations that tuberomammillary neuron firing is maximal (e.g., ref. 90). The discrepancy with data from pharmaco- during wakefulness, suggest that histaminergic systems logic approaches may result from the difficulty to achieve make an important contribution to the control of arousal. selective histamine neuron ablation. The circadian changes in histaminergic neuron activity seem to be directed by two major neuronal inputs arising from Control of Pituitary Hormone Secretion the anterior hypothalamus. The first ones are slow-wave sleep-activated inhibitory GABA- and galanin-containing Histamine affects secretion of several pituitary hormones neurons arising from the ventrolateral preoptic area (12,13); (2,91). Magnocellular neurons of the supraoptic and para- 186 Neuropsychopharmacology: The Fifth Generation of Progress

ventrical nuclei are typically excited, an essentially H1-re- finding consistent with a regulatory role of this receptor in ceptor–mediated response resulting in enhanced blood lev- seizure activity (98). els of vasopressin and oxytocin. Histaminergic neurons are activated during dehydration, parturition, and lactation, and histamine release onto magnocellular neurons partici- Nociception pates in the control of these physiologic processes by the The antinociceptive effects of histidine loads, H3-receptor neurohypophysial hormones (92,93). antagonists, and histamine N-methyltransferase inhibitors, Histaminergic neurons may also participate in the hor- as well as opposite effects of histamine synthesis inhibitors or monal responses to stress. In agreement with this concept, H3 agonists, support the idea that brain histamine inhibits they are activated during various forms of stress and heavily nociceptive responses such as the mouse hot plate jump project to hypothalamic or limbic brain areas (e.g., the (99). In contrast, peripherally acting H3-receptor agonists amygdala or bed nucleus of the stria terminalis) involved prevent nociceptive responses such as mouse abdominal in these responses. Various pharmacologic studies have constriction by inhibiting sensory C-fiber activity (100). shown the participation of endogenous histamine by H1- and H2-receptor stimulation in the adrenocorticotropic hor- mone–corticosterone, prolactin, or renin responses to stressful stimuli such as restraint, endotoxin, or dehydration ROLE OF HISTAMINERGIC NEURONS IN (94). Many histaminergic neurons contain estrogen recep- NEUROPSYCHIATRIC DISEASES tors, project to luteinizing hormone–releasing hormone neurons in preoptic and infundibular regions, and may con- Among the various approaches that tend to establish the implication of other neuronal systems in neuropsychiatric stitute, by H1-receptor stimulation, an important relay in the estradiol-induced preovulatory luteinizing hormone diseases, so far only a few have been applied to histamine. surge (95). Histamine, , and Satiation Antipsychotic Drug Actions

Weight gain is often experienced by patients receiving H1 Overdose of various classic H1 antagonists was repeatedly antihistamines as well as by patients taking antipsychotics reported to result in toxic psychoses with hallucinations re- or antidepressants displaying potent H1-receptor antagonist sembling schizophrenia, and the hallucinogenic potential of properties. These effects reflect the inhibitory role of endog- these drugs has even led to abuse (86). Conversely, metam- enous histamine on food intake mediated by the H1 recep- phetamine, a drug with hallucinogenic potential and to tor, namely, on the ventromedial nucleus (97). Histamine which patients with schizophrenia seem hyperresponsive, neurons projecting to the hypothalamus may be responsible releases histamine in rodent brain areas, an indirect effect for the food intake suppression induced by leptin (70). mediated by stimulation of D2 and not D3 dopamine re- ceptors (77,78). Even more, endogenous dopamine appears to exert a tonic stimulation of histamine neurons because Seizures typical neuroleptics, such as , decrease their ac- The anticonvulsant properties of endogenous histamine tivity. In contrast, atypical neuroleptics, such as , were initially suggested from the occurrence of seizures in enhance histamine turnover, an effect related to 5-HT2 re- patients with , particularly children, after adminis- ceptor blockade and possibly underlying their procognitive tration of high doses of H1-receptor antagonists crossing properties (77). The locomotor activation elicited in rodents the blood–brain barrier, even those agents devoid of anti- by amphetamine and other agonists is attenu- cholinergic activity (86). These drugs, by completely occu- ated by H3-receptor blockade (101). Repeated amphet- pying the H1 receptor, as assessed by positron emission to- administration to rodents that results in behavioral mography studies (30), could block the histamine-induced sensitization to dopamine agonists, a cardinal feature of -current. schizophrenia, is accompanied by enhanced histamine re םreduction of a background-leakage K Drug-induced changes in histamine synthesis, release or lease, a finding that presumably reflects an enhanced tonic metabolism confirmed the role of the endogenous amine dopaminergic influence on histaminergic neurons (77,78). acting through the H1 receptor in preventing seizure activity In one comprehensive study, an enhanced level of t-methyl- elicited by pentetrazol, transcranial electrical stimulation, or histamine, the major histamine metabolite, was detected in amygdaloid kindling . Acquired amygdaloid kindling sus- the cerebrospinal fluid of patients with schizophrenia, who ceptibility appears associated with reduced histamine syn- were either treated or untreated with neuroleptic agents thesis in limbic brain areas (97). In addition, kainic acid–in- (102). duced limbic seizures are accompanied by up-regulation of In several open studies, , an , the H1-receptor mRNA in striatum and dentate gyrus, a was found to improve schizophrenia in patients, a finding Chapter 14: Histamine 187 that remains to be confirmed in control studies. A previous contrast, little is known, so far, about their possible implica- claim of association between polymorphisms of the H2-re- tions in neuropsychiatric diseases and the therapeutic utility ceptor gene and schizophrenia could not be confirmed of psychotropic drugs to affect their activity. 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Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, and Charles Nemeroff. American College of Neuropsychopharmacology ᭧ 2002.