Patrizio Blandina

Therapeutic potential of histamine H3 receptor agonists and antagonists

The histamine H3 receptor was discovered 15 years ago, and many potent and selective H3 receptor agonists and antagonists have since been developed. Currently, much attention is being focused on the therapeutic potential of H3 receptor ligands. In this review, Rob Leurs, Patrizio Blandina, Clark Tedford and Henk Timmerman describe the available H3 receptor agonists and antagonists and their effects in a variety of pharmacological models in vitro and in vivo. The possible therapeutic applications of the various compounds are discussed.

Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats.

1 The effects of histamine and agents acting at histamine receptors on spontaneous and 100 mM K+‐evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving rats, and on cognitive tests are described. 2 Local administration of histamine (0.1–100 μm) failed to affect spontaneous but inhibited 100 mM K+‐stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)‐α‐methylhistamine (RAMH) (0.1–10 μm), imetit (0.01–10 μm) and immepip (0.01–10 μm) mimicked the effect of histamine. 3 Neither 2‐thiazolylethylamine (TEA), an agonist showing some selectivity for H1 receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K+‐evoked release of acetylcholine. 4 The inhibitory effect of 100 μm histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H1 and H2 but not H3 receptors. 5 The H3 receptor‐induced inhibition of K+‐evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX). 6 The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg−1) and RAMH (5 mg kg−1) were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K+‐evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response. 7 These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Histamine receptors in the CNS as targets for therapeutic intervention

Histamine has long been known to trigger allergic reactions and gastric acid secretion. However, it was later discovered that, in the brain, histamine regulates basic homeostatic and higher functions, including cognition, arousal, circadian and feeding rhythms. The sole source of brain histamine is neurons localized in the hypothalamic tuberomammillary nuclei. These neurons project axons to the whole brain, are organized into functionally distinct circuits influencing different brain regions and display selective control mechanisms. Although all histamine receptors (H1R, H2R, H3R and H4R) are expressed in the brain, only the H3R has become a drug target for the treatment of neurologic and psychiatric disorders, such as sleep disturbances and cognitive deficits. In this review, we discuss recent developments in the pharmacological manipulation of H3Rs and the implications for H3R-related therapies for neurological and psychiatric disorders. The legacy of Sir James Black.

Central histaminergic system and cognition.

The neurotransmitter histamine is contained within neurons clustered in the tuberomammillary nuclei of the hypothalamus. These cells give rise to widespread projections extending through the basal forebrain to the cerebral cortex, as well as to the thalamus and pontomesencephalic tegmentum. These morphological features suggest that the histaminergic system acts as a regulatory center for whole-brain activity. Indeed, this amine is involved in the regulation of numerous physiological functions and behaviors, including learning and memory, as indicated by extensive research reviewed in this paper. Histamine effects on cognition might be explained by the modulation of the cholinergic system. However, interactions of histamine with any transmitter system, and/or a putative intrinsic procognitive role cannot be excluded. Furthermore, although experimental evidence indicates that attention-deficit hyperactivity disorder symptoms arise from impaired dopaminergic and noradrenergic transmission, recent research suggests that histamine is also involved. The possible relevance of histamine in disorders such as age-related memory deficits, Alzheimers disease and attention-deficit hyperactivity disorder is worth of consideration, and awaits validation with clinical trials that will prove the beneficial effects of histaminergic drugs in the treatment of these diseases.

Effects of histamine H3 receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia

In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-alpha-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H3 receptor influences the acquisition and not the recall processes. We also investigated the effects of two H3 receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H3 receptor antagonism are not only mediated by relieving the inhibitory action of cortical H3 receptors, but other mechanisms are also involved. Nevertheless, H3 receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release

The basolateral amygdala (BLA) is involved in learning that certain environmental cues predict threatening events. Several studies have shown that manipulation of neurotransmission within the BLA affects the expression of memory after fear conditioning. We previously demonstrated that blockade of histaminergic H3 receptors decreased spontaneous release of acetylcholine (ACh) from the BLA of freely moving rats, and impaired retention of fear memory. In the present study, we examined the effect of activating H3 receptors within the BLA on both ACh release and expression of fear memory. Using the microdialysis technique in freely moving rats, we found that the histaminergic H3 agonists R‐α‐methylhistamine (RAMH) and immepip, directly administered into the BLA, augmented spontaneous release of ACh in a similar manner. Levels of ACh returned to baseline on perfusion with control medium. Rats receiving intra‐BLA, bilateral injections of the H3 agonists at doses similar to those enhancing ACh spontaneous release, immediately after contextual fear conditioning, showed stronger memory for the context–footshock association, as demonstrated by longer freezing assessed at retention testing performed 72 h later. Post‐training, bilateral injections of 15 ng oxotremorine also had a similar effect on memory retention, supporting the involvement of the cholinergic system. Thus, our results further support a physiological role for synaptically released histamine, that in addition to affecting cholinergic transmission in the amygdala, modulates consolidation of fear memories

Interactions between histaminergic and cholinergic systems in learning and memory.

The aim of this review is to survey biochemical, electrophysiological and behavioral evidence of the interactions between the cholinergic and histaminergic systems and evaluate their possible involvement in cognitive processes. The cholinergic system has long been implicated in cognition, and there is a plethora of data showing that cholinergic deficits parallel cognitive impairments in animal models and those accompanying neurodegenerative diseases or normal aging in humans. Several other neurotransmitters, though, are clearly implicated in cognitive processes and interact with the cholinergic system. The neuromodulatory effect that histamine exerts on acetylcholine release is complex and multifarious. There is clear evidence indicating that histamine controls the release of central acetylcholine (ACh) locally in the cortex and amygdala, and activating cholinergic neurones in the nucleus basalis magnocellularis (NBM) and the medial septal area-diagonal band that project to the cortex and to the hippocampus, respectively. Extensive experimental evidence supports the involvement of histamine in learning and memory and the procognitive effects of H(3) receptor antagonists. However, any attempt to strictly correlate cholinergic/histaminergic interactions with behavioral outcomes without taking into account the contribution of other neurotransmitter systems is illegitimate. Our understanding of the role of histamine in learning and memory is still at its dawn, but progresses are being made to the point of suggesting potential treatment strategies that may produce beneficial effects on neurodegenerative disorders associated with impaired cholinergic function.

Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala

We investigated the effects of agents acting at histamine receptors on both, spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the effects of histamine on cognition might be explained by the modulation of cholinergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modulates the spontaneous release of ACh. The addition of 100 mm KCl to the perfusion medium strongly stimulated ACh release, whereas, 0.5 µm tetrodotoxin (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H3 antagonists (ciproxifan, clobenpropit and thioperamide), directly administered to the BLA, decreased ACh spontaneous release, an effect fully antagonized by the simultaneous perfusion of the BLA with cimetidine, an H2 antagonist. Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H1 antagonists failed to alter ACh spontaneous release. Rats receiving intra‐BLA, bilateral injections of the H3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear conditioning, showed memory consolidation impairment of contextual fear conditioning. Post‐training, bilateral injections of 50 µg scopolamine also had an adverse effect on memory retention. These observations provide the first evidence that histamine receptors are involved in the modulation of cholinergic tone in the amygdala and in the consolidation of fear conditioning.

Characteristics of histamine release evoked by acetylcholine in isolated rat mast cells.

1. Histamine secretion from rat mast cells occurs in the presence of nanomolar concentrations of acetylcholine. 2. Intact glycolytic and oxidative metabolism is required for the acetylcholine‐induced histamine secretion. Removal of extracellular glucose, hypoxia, cyanide and monoiodoacetate almost completely inhibit the secretion. 3. The secretion of histamine is dependent on the extracellular H ion concentration and is blocked when the cells are exposed to Na‐deficient media. 4. The order of potency of cholinrgic agonists in evoking the secretion of histamine is oxotremorine > acetylcholine > choline > carbamycholine > nicotine. 5. Atropine competitively blocks the acetylcholine‐induced histamine secretion, indicating the presence of cholinergic muscarinic receptors on mast cells. 6. Dibutyryl cyclic AMP and adrenaline inhibit the acetylcholine‐induced histamine secretion, indicating a regulatory function afforded by cyclic nucleotides in the cholinergic histamine release.

Aspects of histamine metabolism

ConclusionsProgress in learning the role of histamine in physiology and pathology has been impeded by difficulties in accurately measuring histamine and by the deficiencies of methods to measure its metabolites. The availability of specific, sensitive and rapid methods to measure histamine has helped in understanding the role of histamine in disease. Measuring histamine alone may provide an incomplete indication of the role of histamine in disease or in any other process. For histamine is metabolized by multiple pathways, and the kinetics of these enzymatic activities (as well as the rate of synthesis of histamine) determine the steady-state levels of histamine in tissue and in body fluids. Measurements of both histamine and its metabolites would contribute, and may be essential, to the understanding of the role of histamine in disease, just as measurements of the metabolites of other biogenic amines have been critical to understanding of their roles in diseases. Yet another reason that compels measurements of metabolites is evidence that some of the metabolites of histamine are pharmacologically, perhaps physiologically, active.