Postsynaptic H3 receptor

The suggestion of the existence of postsynaptic H3 receptors have not been clarified in relation to pituitary hormone secretion, although the finding in a single study of a stimulatory effect of the H3 receptor agonist RmHA infused centrally on PRL may suggest such an effect - in as much as the effect was prevented by THIOP. 

In addition to presynaptic receptors, autoradiographic studies have indicated the presence of postsynaptic H3-receptor binding sites as well. Chemical destruction of postsynaptic structures in the striatum using quinolinic and kainic acid resulted in a marked decrease of striatal H3-receptor binding sites (Cumming et al., 1991 Pollard et al., 1993 Ryu et al., 1994). Consequently, a major part of the striatal H3-receptors may be located on striatal GABA neurons, representing more than 85% of the striatal efferents (Kita Kitai, 1988). 

Autoradiography and receptor mRNA studies have shown Hi receptors to be located in most of the brain areas innervated by the ascending histaminergic axons, e.g. cerebral cortex, hippocampus, limbic areas and hypothalamus. Their presence in the cerebellum is not accompanied by appropriate histaminergic innervation. Very few are found in the striatum but this region does show a high density of H2 receptors. H2 receptors are also found with Hi in the cortex, hippocampus and limbic areas, but not in the hypothalamus. Although basically presynaptic the H3 receptor is also found postsynaptically in the striatum and cerebral cortex (Pollard et al. 1993). 

Histamine produces its pharmacological actions by three subtypes of receptors the postsynaptic Hi and H2 receptors and the presynaptic H3 receptor. The H3 receptor is mainly located in the central nervous system (CNS), where it acts as an inhibitory autoreceptor in the central histaminergic neuronal pathways [176]. A number of therapeutic applications have been proposed for selective H3 receptor antagonists, including several CNS disorders such as Alzheimer s disease. Attention Deficit Hyperactivity Disorder, Schizophrenia, or for enhancing memory or obesity control. 

When studying the role of various H3 receptor compounds on pituitary hormone secretion some points have to be considered a) are the actions of the compounds related to H3 receptor binding or to a non-specific action, b) are the actions related to an auto- or heteroreceptor or eventually postsynaptic receptor effect of the compounds, and c) are the actions related to an effect known to involve histaminergic neurons. In the following, we will give a short description of the effect of HA in the neuroendocrine regulation of pituitary hormone secretion (Table 1) and focus on the role of H3 receptors in modulation of the secretion of the individual pituitary hormones based on previously published investigations and our own recent experiments. 

In summary, H3 receptors play an important role in the histaminergic regulation of the secretion of ACTH and other POMC-derived peptides since their activation inhibits the hormone response to various physiological stimuli, which is in accordance with the finding that an inhibition of the histaminergic system by blockade of synthesis or postsynaptic receptors exert a similar effect as activation of H3 receptors. 

In summary, the present findings indicate that activation of presynaptic H3 receptors inhibits AVP secretion induced by hyperosmolality - an effect which is similar to and in accordance with that of blockade of HA synthesis or postsynaptic H1 and H2 receptors. 

In isolated perfused rabbit lung, imetit, -a novel selective H3 agonist- was found to inhibit the effect of acetylcholine and capsaicin on capillary filtration (Delaunois et al., 1995). The effect of imetit was reversed by carboperamide, a novel H3 receptor antagonist. On the basis of these data, the authors conclude that H3 receptors could protect the lung against acetylcholine and capsaicin-induced pulmonary edema, via a prejunctional modulatory effect on the C fibers. Moreover, since the response to exogenous substance P was also inhibited by imetit, the presence of H3 receptors at a postsynaptic level -probably on mast cells- was also suggested. 

These data suggest that the contribution of the cholinergic system to the ameliorating effect induced by histamine H3-receptor antagonists is not mediated by histamine H3 hetero receptors, but by postsynaptic histamine H, receptors. This is supported by previous reports that histamine excites cholinergic neurons through histamine H, receptors [30, 31]. 

In some cases, the discovery and characterization of presynaptic receptors established the existence of anew receptor subtype, like the 0C2 adrenoceptor (Dubocovich and Langer 1974 Langer 1974) and histamine H3 receptor (Arrang et al. 1987). It should be noted, however, that the receptor subtypes located presynaptically are also located postsynaptically. The latter should be taken into account in the strategy of discovery and development of new drugs with preferential presynaptic effects. 

Histamine immunoreactive neurons have been identified in the tuberal region of the posterior hypothalamus (tuberomammilary nucleus), projecting to nearly all parts of the brain. Three histamine receptors are known histamine-related functions in the central nervous system (CNS) are regulated at postsynaptic sites by the H and H2 receptors, while the H3 receptor exhibits the features of a presynaptic autoreceptor, mediating the synthesis and release of histamine. The Hi receptor is widely distributed in the CNS. It is present in all areas and layers of the cerebral cortex, limbic system, caudate putamen, nucleus accumbens, thalamus, hypothalamus, mesencephalon, and lower brainstem and spinal cord. The H2 and H3 receptors are also distributed extensively and in a heterogeneous fashion in the CNS. Regarding the role of histamine in the CNS, there is substantial evidence that it plays a role in control of the sleep/wake cycle. Whether the... 

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