Maria Beatrice Passani

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.

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 neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations?

Histamine axons originate from a single source, the tuberomamillary nucleus (TMN) of the posterior hypothalamus, to innervate almost all central nervous system (CNS) regions. This feature, a compact cell group with widely distributed fibers, resembles that of other amine systems, such as noradrenaline or serotonin, and is consistent with a function for histamine over a host of physiological processes, including the regulation of the sleep-wake cycle, appetite, endocrine homeostasis, body temperature, pain perception, learning, memory, and emotion. An important question is whether these diverse physiological roles are served by different histamine neuronal subpopulation. While the histamine system is generally regarded as one single functional unit that provides histamine throughout the brain, evidence is beginning to accumulate in favor of heterogeneity of histamine neurons. The aim of this review is to summarize experimental evidence demonstrating that histamine neurons are heterogeneous, organized into functionally distinct circuits, impinging on different brain regions, and displaying selective control mechanisms. This could imply independent functions of subsets of histamine neurons according to their respective origin and terminal projections.

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

After oral administration, the nonimidazole histamine H3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components.

Endogenous histamine in the medial septum–diagonal band complex increases the release of acetylcholine from the hippocampus: a dual‐probe microdialysis study in the freely moving rat

The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c‐fos in the medial septum–diagonal band (MSA‐DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA‐DB neurons, we used the dual‐probe microdialysis technique to apply drugs to the MSA‐DB and record the induced effects in the projection area. Perfusion of MSA‐DB with high‐KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra‐MSA‐DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA‐DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA‐DB, increased the release of hippocampal ACh, whereas R‐α‐methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA‐DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c‐fos immunoreactivity were significantly more numerous in ciproxifan‐ or thioperamide‐treated rats than in controls, although no colocalization of anti‐c‐fos and anti‐ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus.

The histamine H3 receptor and eating behavior.

Interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity. Eating behavior is regulated by a complex interplay of central neurotransmitter systems, peripheral endocrine stimuli, the circadian rhythm, and environmental cues, all factors that change the behavioral state and alter homeostatic aspects of appetite and energy expenditure. Key factors driving eating behavior are appetite and satiety that are regulated through different mechanisms. Brain histamine has long been considered a satiety signal in the nervous system. Recent observations, however, indicate that histamine does not meet the criteria for being a satiety signal, because augmented histamine release accompanies the appetitive phase of feeding behavior rather than food consumption and satiety. The appetitive phase requires a high and yet optimal arousal state, and the histaminergic system is crucial for sustaining a high degree of arousal during motivated behavior. Histamine H1 receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity; however, from a therapeutic standpoint, no brain-penetrating H1 receptor agonists have been identified that would have antiobesity effects. Despite conflicting preclinical data, insights are emerging into the potential role of histamine H3 receptors as a target of antiobesity therapeutics. The aim of this review is to outline the relevance of the histaminergic system in controlling feeding behavior and evaluate the potential therapeutic use of histaminergic ligands for the treatment of eating disorders.

Cortical acetylcholine release elicited by stimulation of histamine H1 receptors in the nucleus basalis magnocellularis: a dual‐probe microdialysis study in the freely moving rat

Perfusion of the nucleus basalis magnocellularis (NBM) with histamine agonists and antagonists modulates the spontaneous release of cortical acetylcholine (ACh) in freely moving rats. Perfusion of the NBM with Ringer solution containing 100 mm K+ strongly stimulated the spontaneous release of cortical ACh in freely moving rats, whereas perfusion with 1 µm tetrodotoxin reduced cortical ACh spontaneous release by more than 50%. Administration of histamine to the NBM concentration‐dependently increased the spontaneous release of cortical ACh. Administration of H1 (methylhistaprodifen) but not H2 (dimaprit) or H3 (R‐α‐methylhistamine) receptor agonists to the NBM mimicked the effect of histamine. Perfusion of the NBM with either H1 (mepyramine or triprolidine) or H2 (cimetidine) receptor antagonists failed to alter ACh spontaneous release from the cortex, however, H1 but not H2 receptor antagonists antagonized the releases of cortical ACh elicited by histamine and methylhistaprodifen. Local administration of H3 receptor antagonists (clobenpropit and thioperamide) to the NBM increased the spontaneous release of ACh from the cortex; this effect was antagonized by H1 receptor antagonism. Conversely local administration of MK‐801, a noncompetitive receptor antagonist of the N‐methyl‐d‐aspartate receptor, to the NBM failed to alter ACh spontaneous release from the cortex and to antagonize ACh release elicited by histamine. This study demonstrates that activation of histamine H1 receptors in the NBM increases ACh spontaneous release from the cortex.

Effects of DAU 6215, a novel 5‐hydroxytryptamine3 (5‐HT3) antagonist on electrophysiological properties of the rat hippocampus

1 The aim of the present study was to test the effects of DAU 6215 (endo‐N‐(8‐methyl‐8‐azabicyclo‐[3.2.1]‐octo‐3‐yl)‐2,3‐dihydro‐2‐oxo‐1H‐benzimidazole‐1‐carboxamide hydrochloride), a newly synthesized, selective 5‐hydroxytryptamine3 (5‐HT3) antagonist, on the cell membrane properties and on characterized 5‐HT‐mediated responses of pyramidal neurones in the hippocampal CA1 region. 2 Administration of DAU 6215, even at concentrations several hundred fold its Ki, did not affect the cell membrane properties of pyramidal neurones, nor modify extracellularly recorded synaptic potentials, evoked by stimulating the Schaffers collaterals. 3 Micromolar concentrations (15–30 μm) of 5‐HT elicited several responses in pyramidal neurones that are mediated by distinct 5‐HT receptor subtypes. DAU 6215 did not antagonize the 5‐HT1A‐induced membrane hyperpolarization and conductance increase, a response that was blocked by the selective 5‐HT1A antagonist NAN‐190 (1‐(2‐methoxyphenyl)‐4‐[4‐(2‐phtalamido)butyl‐piperazine). Similarly, DAU 6215 did not affect the membrane depolarization and decrease in amplitude of the afterhyperpolarization, elicited by the activation of putative 5‐HT4 receptors. 4 5‐HT increased the frequency of spontaneous postsynaptic potentials (s.p.s.ps) recorded in pyramidal neurones loaded with chloride. In agreement with previous observations, most of the s.p.s.ps were reversed GABAergic events, produced by the activation of 5‐HT3 receptors on interneurones, because they persisted in the presence of the glutamate NMDA and non NMDA antagonists, d‐aminophosphonovaleric acid (APV; 50 μm) and 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX; 25 μm), and were elicited by the selective 5‐HT3 agonist, 2‐methyl‐5‐HT (2‐Me‐5‐HT, 50 μm). 5 The increase in frequency of s.p.s.ps induced by 5‐HT was significantly antagonized by DAU 6215 in 70% of the cases, whereas the 5‐HT3 antagonist always suppressed the effect of 2‐Me‐5‐HT, at concentrations as low as 60 nm. 6 The antagonistic effect of DAU 6215 was also tested on the 5‐HT3‐mediated block of induction of long‐term potentiation (LTP), elicited by a primed burst (PB) stimulation. Extracellular recordings showed that low concentrations (60 nm) of DAU 6215 suppressed the inhibitory action of 5‐HT on PB‐induced LTP, without affecting the 5‐HT1A‐induced reduction in the amplitude of the population spike. 7 These results provide evidence that DAU 6215 is an effective antagonist of the 5‐HT3‐mediated responses in the central nervous system and may offer a cellular correlate for the pharmacological effects of DAU 6215 as an anxiolytic and cognition enhancer.

Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

Significance Several endogenous molecules contribute to the building of a complex network of neural and hormonal signals that align food intake and energy expenditure. Cerebral histamine works as a satiety factor by activating histamine H1 receptor (H1R) in specific hypothalamic nuclei. Indeed, atypical antipsychotics presumably cause obesity by targeting brain H1R. The endogenous lipid messenger oleoylethanolamide (OEA) mediates fat-induced satiety by engaging sensory fibers of the vagus nerve that project centrally. We find that depletion of brain histamine blunts OEA-induced hypophagia in mice. Our study uncovers previously unidentified neural signaling mechanisms involved in the anorectic action of OEA. Our data offer new perspectives for developing more effective and safer pharmacotherapies to treat obesity and ameliorate the profile of centrally acting drugs. Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.