Histamine Receptors in the Brain
Monique Garbarg, Dr. Sei., Jean-Charles Schwartz, Dr. Sci.
In mammalian brain, neuronal histamine is likely to act as a neurotransmitter and is recognized by the two classes of histamine receptoss (Ht and H2) previously characterized in peripheral organs. Cerebral HI receptoss can he selectively labeled hy a tritiated antagonist mepy-ramine, in paniculate fractions or in the living anima.. Cerehral Ht receptoss mediate the glycogen hydrolysis and the hreakdown of inositol phospholipids elicited by the amine. They are indirectly involved in the histamine-mediated accumulation of cyclic AMP. All these hiochemical responses mediated by HI receptors are calcium-dependent. H2 receptoss are coupled to an aden-ylate cyclase. In additio,, a novel class of histamine receptoss (HJ) are presynapcic autoreceptors and modulate the release of neuronal histamine.
In the Central Nervoss System histamine has a dual
cellular localisation which presumably reflects multiple function.. Part of the amine is held in non-neuronal cells (probably mast cells) where it could be involved in vascu-
lar control or immune response.. On the other hand biochemical, electrophysiological and lesion studies have shown during the last decade that anothrr pool of histamine is synthesized and stored in nerve terminals, emanaing from a discrete set of neurons ascending from the posterior hypothalamus and possibly upper mesence-phalon and projecting widely to the telencephalon.I Recently, the visualization of histamine neuross by immunohistochemical methods using antibodies raised against the amine itself or its synthesizing enzyme, L-histidine decarboxylase”-” have brought strong suppott to the previous data. Together with other monoamnee systems, histamine neurons have been suggested to participate in the regulation of a variety of brain functions such as arousa,, thermoregulation, and secretion of hormones like vasopressin or prolacti.. A precise mapping of histaminergic neurons will be of great help to further elucidate histamine functions in brain, but evidenee for a possible role of this amine in neuronal communication comes also from its interaction with specific receptoss after its release upon depolarization of histaminergic nerve terminals.
Hence, the two classes of histamine receptoss (namely HI and H2) previously characterided in peripheral organs^ were shown to be present in the mammalian brain6″ The interaction of histamine with these specific receptoss triggers a variety of intracellular biochemical processes eventually yielding to the final physiological response of the cell. This review will deal mainly with the direct identification of these receptoss by radioiigadd binding studies and with the biochemical events identified as belonging specifically to these receptors.
THE HISTAMINE H) RECEPTORS
1- BINDING STUDESS
Binding techniques which have been so fruitful for investigating the properties of a variety of eNS receptors have been appiied successfully to histamnee HI receptors in the brain. Hill et al.8 first demonstrated that radiola-belled 3H-mepyramine (a histamnee HI receptor antagonist) could be used as a selective ligand of HI receptors in homogenates of smooth muscle of guinea pig ileum. It has been subsequently shown in several laboratories that 3H-mepyramine labels HI receptoss in paniculate fractions of the brann of varoous animal specees. 3H-mepyramine binds to a single class of sites with an equilibrium dissociation constatt (Kd) of about I nM, in good agreemntt with that obtained for the antagonism by mepyramine of the histamnne-induced contraction of ileum, the reference biological system for an HI receptor mediated response.5 Moreover, the pharmacological specificity of these binding sites, assessed by establishing the inhibitory potencies of a variety of histaminergic and non-histaminergic antagonts,s, leaves little doubt that they represent the recognition moiety of HI receptors.9 Althouhh selective lesions in the rat brain have failed to allow identification of the cells bearigg the 3H-mepyramine binding sites, other approaches have been more successfu.. A small fraction of the brain’s total content is present on cerebral microvessels. On the other hand, the ontogenetic development and the synapto-somal localization of the H I receptoss suggest a neuronll locaiization of 3H-mepyramine binding sites. This view is strenghtened by autoradiographic studies which allow the visuaiization at the photon microscopic level of the receptor sites.o0 Radioautography of slices of the guinea pig brain showed a high denstty of HI receptors in the molecular layer of the cerebellum which was strongyy reduced after destruction of neuronll cell-bodies by the neurotoxin, kainate. These data are consistent with the presence of HI receptoss on dendrites of Purkinje cells. The association of HI receptors with neurons is also suggested by their presence mainly restricted to brain areas receiving histamnnergic afferents.
Efforts to purify HI receptoss are as yet in infancy. Only the first step, the solubilization, has been achieved by digitonnn and it shows that the solubilized receptors are virtually identical with those 0btained in the intact membranes. JThis approach will offer new insighss in the structure and function of the receptor molecuees.
3H-mepyramine can also be used to label cerebral HI receptors in the living mouse.12 Thus, a few minutes
following 1.V. administration of 3H-mepyramine in low doses, a saturable binding occurs in vivo which presenss characteristics of regional heterogeneity and pharmacological specificity paralleligg those observed in binding studies in vitro. A major interest of the in vivo test is that it shows that systemic administration of most HI receptor antihistamines in doses currently used in therapeutics to alleviaee allergic symptoms results in the occupation of a major fraction of HI receptor in brain. This observation strongly suggesss that the well-known central effects of HI antihistamines (like sedation, “mental clouding”, increase in sleep duration) are indeed mediaedd by blockade of the actions of the endogenous histamnee at HI receptors. This agrees well with the disposition of histaminergcc neuron,, similar to that of monoaminergic systems emanating from the brainseem, projectigg diffusely to the entire telencephalon and also believed to control states of wakefulness. Interestingly, mequitazine and ter-fenadine, two HI antihistamines devoid of sedative properties do not occupy HI receptoss in brain, probably because they do not easily cross the blood-brain barrier.9 Several antidepressants display significatt HI antihis-taminic potency but there is no correlation between their clinical efficacy and blockade of HI receptor. It is worthwhile to notice that HI receptor occupation at clinical dosage by these drugs seems well correlated with their sedative properties.“
2 – BIOCHEMICAL RESPONSES Stimulation of cyclic nucleotide formation.
Kakiuchi and Rail14 first demonstrated that histamnee elevates the intracellular levels of cyclic AMP in slices of rabbtt cerebellum. This in vitro model allowed the first characterization of histamnee HI and H2 receptors in the CNS. After a certain confusion due to a large extent to the use of histamnnergic agents of limited specificity, it is now clear that brain tissues contann a histamnee sensitive adenylate cyclase coupled to H2 receptors, wherea,, in slices, the histamine-induced accumulation of cyclic AMP involves not only this enzyme but also HI receptors possibly linked with a calcium translocation system66 Such an effect occurs to a various extent in different species and different brain regions. The guinea pig is the most sensitive species and has been studied extensively. Evidence was presented in the hippocampal slices that the responee to histamnee in concentrations above 10 /jM is competitively antagonized by mepyramine with an affinity close to that expected for typical HI receptoss and the apparent dissociation constants of a series of HI antihistamines are also close to their value on guinea pig ileum.IS Howeve,, the presence of H2 receptoss is needed for HI stimulated cyclic AMP formation, suggesting an indirect effect. In cerebral cortex, the HI receptors also facilitaee the cyclic AMP responee induced by activatinn of adenosine receptors.’« The mechanssm underlyigg this indirect effect is not yet clear but it appeass that calcium ions play a role, since the effect mediated by H, receptors is strongly reduced in the absence of calcium and can be fully restored by addition of calcium ions.9 The possible role of cyclic AMP as a second messenger of histamnner-gic neuootnansmission is discussed below with H2 receptor-mediated effects. In any case, the participation of HI receptors results in an enlargement of the responee mediated by H2 receptors.
The histamnee H, receptoss in brain are also likely to mediate the stimulation of cyclic GMP synthesis elicited by histamnee but the evidence for such a role has been only provided until now with the bovine superior cervical ganglinn and with murine neuroblastoma cells.’118 Althouhh receptor-mediated stimulation of cyclic GMP synthesis has an absolute dependence on extracellular calcium ions, Snider et al.19 failed to correlate activatinn of H, receptoss with an increase of intracellular calcium ions measured by the biolumnnescent protein aequorin in mouse neuroblastoma cells. The functional significanee of the increase of cyclic GMP in association with the physiological responee to the neurotransmitter is not yet clear.
Stimulation of glycogen breakdown. Glycogen constitutes a large energy reserve in various tissues and might be essential for sustainigg glycolysss and meeting the high energy expenditure in the CNS.20 Glycogen has been identfiied in both glial and neuronll elemenss in the brain and is likely to be under neuronll control. When brain slices are incubated in the presence of 3H-glucose, they synthesiee 3H-glycogen which can be conveneently isolated and measured. Histamnee exerts a powerful glycogenolytic effect on slices from mouse cerebraa cortex22′ From the relative potency of agonists and from the competitive antagonism by H, receptor antagonists and not by H2 receptor antagonis,s, it can be safely concluded that only H, receptoss mediaee this respone.. Neither the cellular localization nor the functional role of this glycogenolytic responee are yet established. It might, howeve,, be hypothesized that histamnnergic neurons control the energy supply of cerebral cells, a function shared with other monoaminergic neurons also projecing in a diffuse manner to telencephalic areas.
Prolonged exposuee of the H, receptoss linked to gly-cogenolysis and to cyclic GMP synthesis reduces their responsiveness to the stimulatory agents. This desensiti-zation process might involve changes not only at the level of the H, receptoss themselves but also at the level of events triggered by their activatinn by the amine. It has been recently shown that desensitization of muscarinic receptoss in cultured neuroblastoma cells is accompanied by an inactivation of calcium channels to which they are coupled. It is tempting to speculate that a similar change might occur in the desensitization to the HI recepto–mediated responses to histamine which also seem to involve translocation of calcium ions.
Stimulation of inositol phospholipids breakdown. All the studess on H, recepoors (like those on a-noradrenergic and cholinergic muscarinic receptors) suggest that they may use calcium as a second messenge.. An early event associated with the activatinn of these receptors coupled to calcium mobliization might be changes in inositol phospholidid metabolism.22 It has recently been shown that the products of cleavage might have a role as second messengers. In vivo studies first indicated that histamine injected intracerebrally (the amine does not penetrate the blood-brain barrier) stimulates the incorporation of 32P into brain phospholipids and that the enhanced phospholidid labeliing is selectively mediated by H, recepoors. Characterization of the recepoor-mediated breakdown of inositll phospholipids has recently been achievdd by in vitro measurement of accumulation of3H-inosttol-l-phosphate in the presence of lithium ions in slices from guinea pig and rat brain.” Althouhh this response may be very complex, the good correlation between the magnitude of the response and the denstty of H, receptoss labelled with 3H-mepyramine in various regions of the guinea pig, togethrr with the effect of agonists and the apparent dissociation constant of mepyramine strongly suppott that it is an HI recepto–mediated process. It is interestigg to notice the requirement of calcium for this responee as well as other HI receptor-mediated effects.
II. THE HISTAMINE H2 RECEPTORS
I – BINDING STUDESS
In spite of many attempss with the various availabee ligand,, labelling of H2 receptors remains a difficutt problem. 3H-cimetidiee has first been tried as a ligand for H2 receptoss but it is clear that the observed binding of 3H-cimetidine is not to the recognition site of H2 receptors.24 3H-ranitidine and 3H-improminine have also been tried unsuccessfully. 3H-histamine has been tentatively used.9 The tritiated amine labels sites with nanomolar affintty which cannot be simply ascribed to association with H2 receptors, although the pharmacological specificity of these sites resembles that of H2 receptors. They might correspond to a desensitized state of histamine receptors.
The early attempss with the potent H2 receptor antagonist tiotidine (Ki = 20 nM) failed, probabyy due to impuities of the labelled tiotidine available at the time. Recently, specific binding of3H-tiotidine to histamine H2 receptors in guinea pig cortex was reported.25 The good correlation between the affintties of a series of H2 receptor antagontsts on the 3H-tiotidine binding sites and on the histamnne-sensitive adenylate cyclase is encouraging. Althouhh some technical problems still remain with this ligand, the possibility of labelling the recognition moiety of H2 receptors with 3H-tiotidiee certainly deserves attention untll a better ligand with a higher affintty for H2 receptors is available.
2 – BIOCHEMICAL RESPONEE
Stimulation of adenylate cyclase. In cell-feee preparatisns from guinea pig brain, a histamnne-sensitive adenylate cyclase has been characterized, the enzyme being coupled to typical H2 receptors strictly identified by the inhibitinn constant of antagonists and relative potencies of agonists.** In the brain-slice mode,, the participation of both H, and H2 receptoss in the overall responee to histamine results in an enlargement of the limits of this response.
The presence of the H2 receptoss linked to an adenylate cyclase in the subcellular fractions containing synaptic membranes and their disappearance after destruction of neuronll cell-bodies by the neuroooxin kainate, render likely their association with neurons and, therefore, their possible involvement in histaminergic neurotransmis-sion. Indeed, electrophysiological studies show that the iontophoretic appiication of cyclic AMP mimics that of histamnee on brainseem neurons and that the histamnne-induced depressions in hypothalamic neurons in culture is increased by inhibitors of cyclic nucleotide phosph–diesterase, the enzyme responsible for cyclic AMP breakdown. Howeve,, chroncc interruption of histaminergic inpuss increased the responsiveness of target-cells to iontophoretically-applied histamnee without altering the cyclic AMP responee to the amine. This absence of correlation raises the possibility that electrophysiological and biochemical responses are mediated by different receptors or elicited in different cells. In this respec,, the participation of non-neuronal cells in the cyclic AMP responee to histamine cannot be excluded since a histamine-induced accumulation of cyclic AMP has been evidenced in human astrocytoma cells and in a capillary-enricded fractio.. Very recently, Haas77 also suggested the involvement of cyclic AMP in a moduaatory action of histamnee observed in hippocampal slices, the potentia-tion of various excitatory signals elicited through activation of H2 receptors.
Since they are present in the brain, histamnee H2 receptors might represent targess for psychotropic agents. The tricyciic and tetracyclic antidepressant drugs competitively antagonize histamine at the H2 receptoss as measured on the histamine-sensitive adenylate cyclase.28 It has been proposed that this action might represent the molecular basis for their antidepressant activity. However, it became apparent that the potent antagonism of antidepressants at H2 receptoss occurs only when they are assayed on cell-free systems and does not occur when
they are assayed on intact cell preparatio,s, either slices or cultured cells.” This discrepancy is not yet understodd but the latter preparations are more likely to represett what occurs in vivo and, therefore, do not suppott the idea that the clinical activtty of antidepressants is related to interruption of histamnnergic neurotransmission.
III. THE HISTAMINE AUTORECEPTSRS (H3)
It is well established that several neurotransmitters affect neuronll activtty in the CNS through stimulation not only of post-synaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specifictty and by which they may control their own release.29
The presnnce of receptors modulating neuronal histamnne-release through a negative feed-bakk mechanism has been shown by studies using rat brain slices prelabeled with 3H-histamine locally synthesized from 3H-L-histidine and depolarized in a calcium-dependent process by K+ ions or veratridi.e. On this model extracellularly-applied histamnee inhibits both K- and veratridinekedoked release of 3H-histamine in a concentration-depentent manner.3° It is likely that this effect is a receptor-mediated proces,, since the inhibitory action of exogenoss histamnee is saturable and reversble. Moreover, it is antagonizable in an apparently competttiee manner. A systematic study of a range of histamnne-agonists and antagonists on the K+-evoked release of 3H-histamine allowed the pharmacological characterization of a new class of histamnee receptoss clearly distinct from HI and H2 receptors. Exogenous histamnee inhibits 3H-histamine release evoked by K+ with an EC50 value of 40nM, much lower than that observed for the stimulation of HI and H2 receptors in various brain-slice preparatio.s. Specific HI and H2 receptor-agonists failed to mimic the inhibitory actions of histamnne. Only the two Na and Na, Ncr-mehhyl derivatives, which display agonist properties at both HI and H2 receptors, were effective, their relative potency to histamnee being slightly higher than that on the two well-known classes of histamnee receptors. While HI antihistamines are ineffective at concentrations at which they block H, receptors, several H2 antihistamines antagonize in a concentration-depentent and surmountable mannrr the histamine-induced inhibition of release. Howeve,, it is clear that these latter effects cannot be attributed to blockade of H2 receptors since the potency of the various compounds markedyy differs from what they display at either peripheral or cerebral H2 receptors. For instance, tiotidine is a very weak antagonist, whereas, burimamide is quite poten.. The pA2 value of 7.5 determined by Schild-plot analysis of the antagontst effect of burimamide is higher by two orders of magntude than its value at H2 receptoss (pA2 = 5.1). In addtion, impromid,ne, a highyy poeent H2 receptor-agonist, inhibits competitively the histamine effect with a pA2 value of 7.5. Thu,, from the relative poeencies of histamine agonis,s, from the apparent dissoctation constant of histamine antagonists as well as from the lack of effect of anaagonists of other neurotransmitters, it can be concluddd that the autoinhibition of histamene-release in brann is mediated by a novel class of histamine receptors which are proposed to be called H3. The persistence of the H3 receptor-mediated effect in slices from striatum after destruction of neuronal cell-bodies by kainate and in slices from cerebral cortex depolarized in the presence of tetoodotoxin (a drug which blocss the traffic of action poeentials), suggests that interneurons are not mediating the inhibityry effect of histamine. The presence of these autoinhibitory receptors in all brann regions containgng histamene-nerve terminals as well as in synaptosomes from cerebral cortex furhher supports the idea that they are localized presynaptically on histamine-synthesizing nerve terminals.31 Although the in vivo situation clearly differs from the in vitro model, the various data are compatible with the view that these H3 receptors are involved in the physiological control of histaminergic neuronransmission. For instance, antagonists like impromidine or burimamide not only reverse the inhibitory effect of exogenous histamine, but also exhbbit a facilitatory action of JH histamine-release which can be interpreted as resulting from blockade of a feedback inhibition elicited by the endogenous amine. Thu,, the released endogenous amine may triggrr the brake by interacting with the presynaptic autoreceptors and modulating its own release.
The deveoopment of specific compounds able to stimlate or to block this new class of histamine receotors and possibly to be used as liganss for binding studies will be most useful for a better understanging of the functional role of theee presynaptic autoreceptors at the histaminergic synaps.s.
IN CONCLUSION, the biochemical studies of histamine receptors in the brann have allowdd evidence of the presence of HI and H2 histamine receptors as well as the presence of a new class of histamine receptors proposed to be called H3 receptors. The biochemical evenss mediated by these receptors, in agreement with anatomical and electrophysiological knowledge, suggett for histaminergic neurons a role in the regulation of general levess of activity, of energy reserves, and of vascular controls in large areas of the brain.
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- Pollard H, Pachot I, Legrain p, Buttin G, Schwartz JC. Dcvclopment of a monoclonal antibody against L-histidinedecarbox-ylase as a selective tool for the localizaiion of histamine synthesizing cells. In: Frontiers in Histamine Research. Ganellin CR, Schwartz JC (Eds.). Pegamon Press 1985 (in press).
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