Neurochemical and neuropharmacological aspects of histamine receptors

Neurochemical and neuropharmacological aspects of histamine receptors

Neuro~heml~tr~ Internattonal, Vol 4 No 2 3, pp q7 99, 1982 Printed m Great Britain 0197-0186 82,020097-03503 00,'0 Pergamon Press Ltd CRITIQUE NEURO...

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Neuro~heml~tr~ Internattonal, Vol 4 No 2 3, pp q7 99, 1982 Printed m Great Britain

0197-0186 82,020097-03503 00,'0 Pergamon Press Ltd


As D r Taylor's review makes clear, the considerable current interest in histamine m the brain is centred firmly on its possible role as a neurotransm~tter The advances made over the last few years, s u m m a n s e d in the review, have been considerable, but whether these stu&es really "indicate that histamine endogenous to the C N S has a function distract from that observed in non-neural tissues, namely that of a transmitter" is still a matter for some debate. Certainly many of the necessary elements are there' biochemical and electrophys~ologxcal responses to histamine have been described, Ha- and H2-receptors are present and histamine in the neuronal pool, which appears to be assocmted with specxfic hlstldme decarboxylase and which shows a rapid turnover, has at least some of the properties which would be anticipated if it were to fill a central functional role. The difficulty, as far as gaining any real insight into function xs concerned, is that there has been disappointingly little progress m hnkmg evidence obtained at different levels and in relating th~s to the neuroanatomy. F o r example, histamine can be shown to produce certain biochemical effects through an action on defined receptors, but in the intact brain do these receptors ever see enough histamine for them to be activated and, if so, what are the functional consequences 9 P r o b a b l y the biggest gap in our knowledge at the m o m e n t is in the neuroa n a t o m y There is no simple fluorescence technique for tracing possible hlstammerglc pathways, such as there is for the catecholamlnes, and it seems that nobody has yet managed to produce a specific antibody to histamine or hlstldlne decarboxylase, which would allow the use of lmmunofluorescence methods Dramatic progress may be anticipated when these tools become available, but In the meantime, the anatomical evidence has been derived mainly from changes in hlstldlne decarboxylase levels in given brain areas following specific lesions (Schwartz, Pollard and Quach, 1980). to a lesser extent from electrophyslologlcal

studies (Schwartz, 1979) and, more recently, from autoradlograph~c studies of receptor distribution. This last hne of evidence is hmlted so far to the elegant studies of K u h a r and his collaborators (Palaclos, Wamsley and Kuhar, 19811 on the distribution of t n prohdlne-sensltlVe [ 3 H ] m e p y r a m l n e binding to rat brain slices This is the most precise information on receptor distribution currently avadable, but, as in any binding study, the questxon must still be asked whether the binding sites all represent functtonal receptors Guinea-pig cerebellum is a tissue of particular interest m this respect In m a n and rat the cerebellum Is a m o n g the regions with the lowest density of h~stamlne Ha-receptors, but in the guinea-pig the cerebellum is the area richest in Ha-receptors, with a preponderance in the molecular layer However, there is as yet no reported biochemical or physiological response to histamine in guinea-pig cerebellum and this region has few mast cells and little hlstldlne decarboxylase (Palaclos, Young and Kuhar, 1979) O n e is forced to wonder whether some or all of these receptors might not come under the heading of "evolutionary debris" and either never be exposed to significant a m o u n t s of h~stamme or indeed simply not be functzonal It may become clearer whether the cerebellar Ha-receptors are likely to be exposed to sagnlficant a m o u n t s of histamine when it becomes possible to locahse the n o n - m a s t cell storage sites However, it must be noted that the studies on the effects of longterm administration of H l-antihistamines described In the review do provide a rather indirect test of whether the receptors are exposed chronically to histamine If they were, then one might expect receptor n u m b e r to be normally somewhat down-regulated and that extended administration of an antagonist would produce an Increase m receptor n u m b e r There is no evidence that thxs occurs m guinea-pig cerebellum, but in hypothalamus, a region of particular interest in con97



sldering possible functional roles of histamine (Schwartz, 1979), there could be such an effect In this respect the two studies on long-term regulation cited in the review do not differ as much as may appear at first sight In the rat study there was a clear-cut effect In the guinea-pig effects were observed, but not always Clearly this region deserves further study The assessment of functionality from the effect of long-term treatment with antihistamines is a very mdirect approach and one which for several reasons could easdy given an answer that was falsely negative (Hdl, Hiley and Young, 1981) It is disappointing that hgand binding stu&es have so far failed to provide any indication of the functional response to which the receptor sates are coupled Such studies are in any case limited at the minute to Ha-receptor hgands, since, as Dr Taylor has emphaslsed, there is no satisfactory hgand for the H2-receptor The hope must be that since agonists produce conformatlonal changes m the receptor, these may be mirrored in their binding characteristics as deduced from the inhibition of receptor-specific [3H]hgand binding Further. there must be a prospect that couphng to dafferent effectors may be differentially affected by drugs, in the way that with receptors coupled directly to adenylate cyclase agonlst binding as normally modulated by G T P The effect of G T P on histamine inhibition of [3H]mepyramine binding ~s really rather modest and at as not at all clear how it is to be interpreted There is no ewdence of a &rect coupling between Hi-receptors and adenylate cyclase The H~-stlmulatlon of cyclic A M P accumulation m slice preparations seems to be an indirect effect and to reqmre the presence of a directly acting agomst This can be demonstrated very clearly m shces of guinea-pig cerebral cortex, where histamine alone has httle effect, but markedly potentiates the action of adenosine (Hill, Daum and Young, 1981) It must also be noted that the fact that several histamine Hi-receptor mediated effects, such as cyclic A M P accumulation, stimulation of glycogenolysis and hastamme-mduced release of catecholamines (Subramanlan and Mulder, 1977), probably an HIresponse, require an intact cell preparation introduces a potential compllcat~on m the &rect comparison of binding and response data. Binding of [3H]hgands to tissue slices is technically possible, but much less easy to carry out than binding to tissue homogenates However, ~t is by no means certain that receptor conformation will be controlled an the same way in membrane fractions from tissue homogenates as in the intact cell, where quite apart from other differences, the two sides of the membrane are exposed to medm

of differing composition As Dr Taylor has pointed out there is no evidence of any changes in Ha-antagonist binding, but it is by no means certain that the same will be true for agonlsts With this potential difficulty in mind the value of having a &sperse, intact cell preparation with a well-characterlsed baochemlcal response to histamine, such as the neuroblastoma cell hne investigated extensively by Rlchelson and his collaborators, including Dr Taylor, becomes very apparent Some progress has been made an developing cellfree preparataons of guinea-pig cerebral cortex m which a histamine Hi-response can be measured (Daly, McNeal, Partlngton, Neuw~rth and Crevehng, 1980; Psychoyos, 1981), but it remains to be estabhshed to what extent they can be used as models of the intact cell The value of intact preparation has been discussed with reference to H a-agonlst binding, since as noted already the Ha-receptor is, regrettably, the only histamlne receptor for which there is a satisfactory [3H]ligand However, the most striking illustration of the potentml problems assocmted wath the use of tissue homogenates concerns the H2-receptor Dr Taylor has discussed an his review the high affinity which amItrlptyline and a number of other antidepressant drugs have for the H2-receptor, as indicated by the inhlbat~on of the histamine-stimulated adenylate cyclase activity an a cell-free system However, ff the same experiments are performed using tissue slices, then amltriptyhne appears to be much less potent as an H2-antagonist, although the affimty of cimetidine and metlamide remain the same (Tuong, Garbarg and Schwartz, 1980) The explanation for th~s effect is not known, but it seems unlikely to be an oddity of the slice preparation used, since a similarly low potency of amitrlptyhne has been reported against the positive chronotropic response to histamine m guinea-pig right atrmm and against histamme-stlmulated gastric acad secretion in the m v i t r o lumen-perfused mouse stomach (Angus and Black, 1980) Clearly more than a little caution is necessary In evaluating the role of H2-receptor blockade in the chnical response to antidepressants Perhaps one brief plea may be made on the subject of nomenclature The use of both [3H]pyrilamine and [3H]mepyramine, the American and European names for the same compound, would seem to be a potential source of confusion for those not famdiar with the field The [3H]hgand was first introduced for HIreceptors under the name of [3H]mepyramme (Hill, Young and Marrlan, 1977) and was used under this name for subsequent binding studies on both sides of the Atlantic Clearly we have a highly partisan point

Neurochemical and neuropharmacologlcal aspects of histamine receptors of view, but st would seem better to use just one name For all the excitement and progress of recent years the sanguine view has to be that there is stdl very httle concrete evidence that histamine plays any sigmficant role in normal brain function. One ~s reluctant to beheve that the amine, with its associated enzymes and receptors is hke an actor w~th a stage and the scenery, but with no play In pathological states h~st a m m e released from mast cells could have ~mportant effects, although these could well be primarily on the vasculature (Schwartz et a l , 1980) Perhaps too much emphasis has been on the possible involvement of hlst a m m e as a 'neurotransm~tter" This tends to suggest a s~mple system of h~stammerg~c nerves releasing h~stamlne onto postsynaptlc receptors to produce either excitation or inh~bmon This could turn out to be the case, but the relation of h~stamme to neural function could equall) well be more subtle The many examples now avadable of the coexistence of neuroactive molecules within the same nerve axon calls to mind old reports, recently re-exammed (MacDonald, Meze~ and Mezel, 1981), that histamine is associated w~th neural elements in the scmttc nerve. It ~s qmte possible that histamine m the CNS may coexist m neurones w~th other neuroeffectors and whether ~t could then be regarded as a n e u r o t r a n s m i t t e r or neuro m o d u l a t o r mtght depend on definmon, on just which cells the histamine receptors were located and on what the response to receptor activation was Alternatwely, histamine may be assocmted, at least in part, with other neural elements, such as ghal cells, m which case its effects m~ght be more obviously modulatory It ~s not &fficult to see why histamine m the CNS continues to be such a fascinating and challenging puzzle


REFERENCES Angus, J A and Black, J W (1980) Pharmacological assay of car&ac H2-receptor blockade by amltnptyhne and lyserglc aod dlethylamlde Czrculatzon Res 46, 64-69 Daly, J W., McNeal, E, Partmgton, C, Neuwlrth, M and Crevehng~ C R (1980) Accumulations of cychc AMP m adenine-labeled cell-free preparations from guinea-pig cerebral cortex role of ct-adrenerglc and H~-hlstammerglc receptors J Neurochem 35, 326-337 Hdl, S J, Daum, P and Young~ J M (1981) Affinities of histamine H~-antagomsts m gmnea-plg brain slmdanty of values determined from [3H]mepyramlne binding and from inhibition of a functional response J Neurochem 37, 1357-1360 Hdl, S J, Hdey, C R and Young, J M (1981) Extended mepyramme treatment and histamine H~-receptors in guinea-pig brain Eur J Pharmac 71,421~428 Hdl, S J, Young, J M and Marnan, D H (1977) Specific binding of [3H]mepyramlne to histamine H1 receptors m intestinal smooth muscle Nature 270, 361-363 MacDonald, S M, MezeL M and Mezel, C (1981) Effect of Wallermn degeneration on h~stamme concentration of the peripheral nerve d Neurochem 36, 9-16 Palaoos, J M, Wamsley, J K and Kuhar, M J (1981) The distribution of hlstamme Hi-receptors m the rat brain an autoradlographlc study Neurosctence 6, 15-37 Palaclos, J M, Young, W S and Kuhar, M. J (1979) Autoradlograph~c locahzatlon of H 1-histamine receptors m brain using 3H-mepyramme prehmmary studies Eur J Pharmac 58, 295--304 Psychoyos, S (1981) Antidepressant mhlbmon of H1- and Hz-hlstamme-receptor medmted adenylate cyclase in [2-3H]adenme-prelabeled vesicular preparauons from guinea-pig brain Blochem Pharmac 30, 2182-2185 Schwartz, J C (1979) Histamine receptors m brain Ltfe Sc~ 25, 895-912 Schwartz, J C, Pollard, H and Quach, T T (1980) Histamine as a neurotransmltter in mammahan brain neurochemlcal evidence J Neurochem 35, 26-33 Subramaman, N and Mulder, A H (1977) Modulation by histamine of the efflux of ra&olabeled catecholamlnes from rat brain slices Eur J Pharmac 43, 143-152 Tuong, M D T, Garbarg, M and Schwartz, J C (1980) Pharmacological speclficlty of brain histamine H2-receptors differs in intact cells and cell-free preparatlons Nature 287, 548-551