Lucia Bacciottini

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.

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.

Local GABAergic modulation of acetylcholine release from the cortex of freely moving rats.

Cortical perfusion with GABA agonists and antagonists modulates the spontaneous release of cortical acetylcholine and GABA in freely moving rats. Twenty‐four hours after implantation of a dialysis fibre, cerebral cortex spontaneously released acetylcholine (3.8 ± 0.2 pmol/10 min) and GABA (6.6 ± 0.4 pmol/10 min) at a stable rate. Local administration of GABA (1 or 5 mm) or the GABAA agonist muscimol (25 or 50 μm) had no effect on the spontaneous release of acetylcholine. However, bicuculline (1–25 μm), a GABAA antagonist, added to the dialysis perfusate, elicited a concentration‐dependent increase of acetylcholine release to approximately double that of control. This effect of bicuculline (25 μm) was completely prevented by coperfusion with muscimol (50 μm). Local administration of the GABAB receptor agonist baclofen (10 or 50 μm) elicited a concentration‐dependent increase in spontaneous acetylcholine release with a maximal increase of about 60%. Intracortical administration of baclofen also decreased the spontaneous release of GABA. The GABAB receptor antagonist CGP 35348 (1 mm), administered alone for 20 min through the dialysis fibre, was without effect on spontaneous acetylcholine release; however, it completely blocked both the baclofen‐induced increase in acetylcholine release and the decrease in GABA release. These results suggest that cortically released GABA exerts a tonic influence on cholinergic activity.

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.

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.

GABAergic mechanism in histamine H3 receptor inhibition of K+-evoked release of acetylcholine from rat cortex in vivo

Autoradiographic studies have suggested that the presence of H3 receptors, initially detected as autoreceptors inhibiting histamine release [1], is not restricted to histaminergic neurons [2–4]. Accordingly, functional studies have shown that H3 receptors modulate the release of several neurotransmitters, including acetylcholine (ACh) in vitro [5], and in vivo [6]. The present study assessed the location of H 3 receptors modulating ACh release.

Morphine withdrawal in cortical slices: suppression by Ca2+-channel inhibitors of abstinence-induced [3H]-noradrenaline release

1 The effects of morphine withdrawal were evaluated in vitro by monitoring the actions of naloxone on the depolarization‐induced release of [3H]‐noradrenaline (NA) in cortical slices taken from naïve or dependent rats. The effects of dihydropyridine molecules acting on Ca2+‐channels (nimodipine and Bay K 8644) were also studied in this model. 2 Naloxone (10−8‐10−5 M) dose‐dependently enhanced the K+ induced release of [3H]‐NA in slices taken from dependent rats, but failed to modify the [3H]‐NA release from ‘naïve’ slices. 3 The naloxone‐induced potentiation of release was significantly reversed by nimodipine (10−8‐10−6 M). These doses of nimodipine did not change [3H]‐NA release (both basal and K+ induced) in preparations obtained from naive rats. 4 Bay K 8644 potentiated the K+‐induced [3H]‐NA release from cortical slices taken from naïve rats to a similar extent as that of naloxone in dependent rats. 5 These results suggest that the naloxone potentiation of the depolarization‐induced [3H]‐NA release in slices taken from dependent rats may be considered a model of morphine withdrawal in vitro. In this model dihydropyridine Ca2+‐channel antagonists suppress morphine‐withdrawal effects in a similar manner to observations made in vivo.

H3 receptor modulation of the release of neurotransmitters in vivo

Publisher Summary In the mammalian brain, histamine is involved in the regulation of numerous physiological functions, including the modulation of memory and synaptic plasticity. Cholinergic systems have been closely linked to cognitive function, but acetylcholine (Ach) is unlikely to be the only neurotransmitter important for cognition. The disruption of cholinergic function is the characteristic of aging and Alzheimers disease, however, these changes typically occur within the context of systems alterations of other neurotransmitters, including noradrenaline, dopamine, serotonin, gamma amino butyric acid (GABA), several neuropeptides, and histamine. Thus, cholinergic dysfunction might well interact with dysfunctions in other neurotransmitter systems to produce additive or even synergistic effects on cognition. Accordingly, the role of interactions between ACh and other neurotransmitters affecting cognition is of considerable interest. Because cognitive deficits might be related to reduce availability of ACh in the synaptic cleft, H 3 receptor activation, by moderating ACh release, would be expected to impair learning and memory. Another histamine H 3 receptor agonist, immepip, also impairs animal performance in the olfactory, social memory test, based on the recognition of a juvenile rat by a male, adult, and sexually experienced rat. Conversely, H3 receptor antagonists, such as thioperamide and clobenpropit, may provide a novel approach to restoring deficits in cognitive functions. The reduction of choline uptake into the brain of older adults may be a contributing factor to late life onset of neurodegenerative, particularly dementing, illnesses in which cholinergic neurons show special susceptibility to loss.

Thioperamide and cimetidine modulate acetylcholine release from the amygdala of freely moving rats

The amygdala is a brain structure involved in the cognitive evaluation of the emotional content of complex cues [1]. The acquisition of characteristic responses to aversive events depends on the integrity of the amygdala. The basolateral nuclei, which receives major inputs from cortical and subcortical sensory areas [2], also receives cholinergic innervation nucleus from the nucleus basalis magnocellularis and histaminergic innervation from the hypothalamus. Autoradiographic and immunohistochemical studies have shown high densities of both H3 [3] and muscarinic receptors in this brain region [4]. This study investigates whether the histaminergic system modulates the release of acetylcholine (Ach) in the amygdala of unrestrained rats. Modulation of cholinergic transmission in the amygdala may be important for the acquisition or expression of relevant behaviours.