H3 heteroreceptor

Schlicker, E., Malinowska, B., Kathmann, M. and Gothert, M. Modulation of neurotransmitter release via histamine H3 heteroreceptors. Fundam. Clin. Pharmacol. 8 128-137,1994. 

The term "H3 receptor" has been coined by Arrang et al.1 H3 receptors are located on paracrine cells and on neurones activation of H3 receptors usually causes inhibition of the release of the respective mediator or neurotransmitter. The receptor characterized by Arrang et al.1 is an example of an autoreceptor, i.e. of a receptor via which the transmitter released from a given neurone influences its own release. H3 receptor-mediated inhibition of the release of transmitters other than histamine has also been described such receptors are known as heteroreceptors. The present review will focus on H3 heteroreceptors in the central nervous system (CNS) in separate chapters of this book, H3 autoreceptors, H3 heteroreceptors in the neuroendocrine system as well as H3 receptor-mediated modulation of transmitter release in vivo will be considered. A separate article will also deal with H3 heteroreceptors in peripheral tissues although an example of an H3 receptor in the retina will be covered in our chapter, due to the close relationship between CNS and retina2. 

In the first part of our chapter the occurrence of H3 heteroreceptors in the CNS and in the retina will be described. Then the location of the H3 heteroreceptors will be discussed. (The term "heteroreceptor" will be used in a relatively broad sense in this article, i.e. regardless of whether the presynaptic location on the nerve endings themselves has been proven or not.) Next, interactions between H3 heteroreceptors and other types of presynaptic receptors will be considered. Finally, some general remarks with respect to H3 heteroreceptors as targets for new drugs will be given. 

Fig. 1. Occurrence of H3 receptors inhibiting release of acetylcholine, of amino acid and monoamine neurotransmitters in the mammalian CNS in vitro. The schematic drawing represents a midsagittal section of the human brain three areas with a more lateral position are shown by broken line (substantia nigra and part of the hippocampus and of the striatum). For each of the six regions of the CNS (subregions given in brackets), in which H3 heteroreceptors have been identified, the neurotransmitter(s) and the species are indicated. The superscripts refer to the numbers of the papers as listed under References. Own unpublished data suggest that an H3 receptor-mediated inhibition of noradrenaline release also occurs in the human cerebral cortex and hippocampus and in the guinea-pig cerebral cortex. Note that a presynaptic location has not been verified for each of the H3 heteroreceptors or has been even excluded (for details, see Table 1). Abbreviations ACh, acetylcholine DA, dopamine GABA, y-aminobutyric acid Glu, glutamate 5-HT, 5-hydroxytryptamine, serotonin NA, noradrenaline...

ARE THE RELEASE-INHIBITING H3 HETERORECEPTORS LOCATED PRE-SYNAPTICALLY ON THE RESPECTIVE NEURONES ... 

Standard superfusion and electrophysiological techniques do not allow to decide whether an H3 heteroreceptor involved in the inhibition of release of a given transmitter is actually located presynaptically (i.e. on the axon terminals) of the respective neurone. Recent (unpublished) data from our laboratory may serve to illustrate this point. In guinea-pig cerebral cortex slices, noradrenaline release is inhibited by histamine via H3 receptors and facilitated via H2 receptors. Using an appropriate technique (see next paragraph) we found that only the H3 but not the H2 receptor is located presynaptically. 

Table 1. Location of H3 heteroreceptors inhibiting the release of monoamines, acetylcholine and glutamate in the brain. To prove or disprove the presynaptic location of H3 receptors, transmitter release was studied in isolated nerve endings (synaptosomes) or in brain slices superfused with K+-rich Ca2+-free medium containing tetrodotoxin (TTX) (in the latter case, transmitter release was evoked by introduction of Ca2+ ions into the medium). The experimental approaches used in the electrophysiological study to show the presynaptic location of H3 receptors on glutamatergic neurones are described in the text.

Axon terminals are usually endowed with several types of presynaptic receptors which do not act independently. It has been described, in particular, for noradrenergic neurones that activation of a given presynaptic receptor blunts the effect mediated via another type of presynaptic receptor32-3 activated subsequently. H3 heteroreceptors on noradrenergic neurones also participate in such receptor interactions. When, e.g., the... 

We do not know whether the interactions between the presynaptic receptors occur on the level of the receptors or on a site beyond the receptor level, e.g. on the level of G proteins, ion channels or other second messengers. Such receptor interactions may explain drug interactions in vivo. They are also of importance for planning in vitro experiments. H3 receptor-mediated effects in superfused slice preparations are frequently small the inhibitory effect on NA and DA release can be increased by simultaneous blockade of the respective autoreceptor. There are even examples of H3 heteroreceptors which could only be identified if the respective autoreceptor was blocked3 12,36. 

If one considers H3 receptor agonists as potential drugs, one has to realize that H3 heteroreceptor-mediated effects are frequently small or moderate. In addition, one has to take into consideration that the release of at least six transmitters is affected and that the effects occur in at least six regions of the CNS (Fig. 1). On the other hand, it is so far unknown whether all the examples of H3 heteroreceptors identified in animals also occur in humans. Moreover, one must be cautious when extrapolating from in vitro data to the situation in vivo. To give an example. Clonidine, which affects presynaptic a2-adrenoceptors on several types of neurones and in a variety of CNS regions, became a very useful drug for the treatment of essential hypertension and for some other indications. 

Histamine H3 receptors are not only involved in the inhibition of the release of histamine itself ("autoreceptors") but, in addition, also in the inhibition of the release of other neurotransmitters ("heteroreceptors"). Such an H3 heteroreceptor-mediated... 

Schlicker E (1997) Histamine H3 heteroreceptors in the CNS. In Neurobiology of Histamine (G Prell ed) Humana Press, Totowa, NJ, USA, in press. 

MODULATION OF CATECHOLAMINES AND SEROTONIN RELEASE MEDIATED BY HISTAMINE H3 HETERORECEPTORS... 

The available data indicate that systemic administration of H3 receptor agonists oppose the stimulatory effect of endogenous HA on PRL secretion and that this effect, which is prevented by concomitant blockade of the H3 receptors, occurs on presynaptic histaminergic neurons rather than on other aminergic neurons. At least, the effect is not exerted via activation of H3 heteroreceptors on serotonergic neurons. 

However, receptor autoradiography and in vitro studies have suggested that H3 receptors are located on other aminergic neurons in the brain. Since amines such as serotonin and catecholamines are involved in the regulation of pituitary hormone secretion, it is obvious that an action of the H3 receptor compounds may be exerted via these H3 heteroreceptors. Only few studies have evaluated this heteroreceptor action. It has been excluded that the effect of the H3 receptor agonists is due to an effect on H3 receptors located on serotonergic neurons, while an effect on catecholaminergic neurons has yet not been excluded. 

In relation to the monoaminergic systems we observed that clobenpropit increased turnover rate of noradrenaline only in some brain regions (17), although histamine H3 heteroreceptors modulate the releases of noradrenaline, dopamine, and serotonin [23-26]. Thus, it appears that the contribution of histamine H3 hetero receptors on the modulation of monoaminergic neurotransmitters may be minor, just being similar to the cholinergic system. 

So far, constitutive activity of presynaptic H3 heteroreceptors has not been described. 

They were the first presynaptic H3 heteroreceptors to be discovered (in guinea pig mesenteric artery Table 1). They mediate inhibition of transmitter release from many noradrenergic neurons, peripheral as well as central (Table 1). They may be activated by histamine from mast cells, as happens in the heart upon myocardial ischemia (see Section 3.10). In the CNS an input of endogenous histamine has not been demonstrated (see references in Table 3). For example, the release of noradrenaline in the hippocampus of freely moving rats remained unchanged upon local... 

Like D2-like heteroreceptors (Section 2.4), the H3 heteroreceptors on noradrenergic terminals may interact with terminal 0G2 autoreceptors preactivation of one receptor attenuates the effect obtainable by activation of the other (see Schlicker and Gothert 1998). 

The inhibitory H3 heteroreceptors on dopaminergic nerve terminals in mouse striatal slices were not activated by endogenous histamine under the experimental conditions chosen, since their blockade did not enhance the release of dopamine (Schlicker et al. 1993). In the rat nucleus accumbens in vivo, however, indirect evidence (an histamine-evoked increase in acetylcholine release) suggests that dopamine release is permanently inhibited by endogenous histamine (Prast et al. 1999a see Section 3.6). 

Presynaptic H3 heteroreceptors, when activated, inhibit the release of transmitter from several peripheral cholinergic neuron systems, probably preganglionic as well as postganglionic parasympathetic (Table 3). The receptors may be activated by histamine secreted from mast cells. 

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