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

Giovannini, Maria Grazia; Bartolini, L.; Bacciottini, Lucia; Greco, L.; Blandina, Patrizio

doi:10.1016/s0166-4328(99)00063-7

Cited by 96 publications

(54 citation statements)

References 43 publications

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“…These deficits were reminiscent of those produced by the nonselective muscarinic antagonist scopolamine or by ligands that impair cognition by dysregulating cholinergic neurotransmission at the level of the septohippocampal pathway. [42][43][44][45]49,50 Dysregulated acetylcholine release in response to environmental stimuli and deficits in the passive avoidance paradigm are not likely to be because of nonspecific phenotypic alterations such as hyperlocomotion in the KO mice. In fact, M4-KO mice that display increased basal locomotor activity 9 do not show deficits in the passive avoidance, whereas M2-KO mice, that perform poorly in the passive avoidance test, display normal locomotor activity (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

et al. 2003

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Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post-and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2-and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2-and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.

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Section: Discussionmentioning

confidence: 99%

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

et al. 2003

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“…Administration of thioperamide, histamine, or histidine, decreased investigation time of a juvenile rat by an adult rat while immepip or inhibition of histamine synthesis by afluoromethylhistidine prolonged recognition time (Prast et al, 1996). However, H 3 receptor blockade might be beneficial under condition of cognitive impairments caused by cholinergic dysfunction (Miyazaki et al, 1995a(Miyazaki et al, , b, 1997Blandina et al, 1996Blandina et al, , 1998Gulat-Marnay et al, 1989a, b;Giovannini et al, 1999;Molinengo et al, 1999). In a two-arm maze using a metal box and a glass bottle as objects in the retention trial and two identical objects in the first trial, H 3 receptor blockade antagonized scopolamine-induced object recognition impairments and object recognition impairments at 90-and 120-min intertrial intervals at which male and female rats, respectively, did not exhibit object recognition anymore in this version of the test .…”

Section: Discussionmentioning

confidence: 99%

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

Bongers

Leurs

Robertson

et al. 2003

Neuropsychopharmacol

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Increasing evidence supports a role for histamine as a neurotransmitter and neuromodulator in emotion and cognition. The H 3 receptor was first characterized as an autoreceptor that modulates histamine release and synthesis via negative feedback. Mice deficient in apoE (Apoe -/-) have been used to define the role of apoE in brain function. In the present study, we investigated the possible role of histamine H 3 -receptor-mediated signaling in anxiety and cognition in mice Apoe -/-and wild-type mice. H 3 antagonists increased measures of anxiety in wild-type, but not Apoe -/-, mice. In contrast, H 3 antagonists similarly impaired object recognition in wild-type and Apoe -/-mice. In Apoe -/-mice, reduced negative feedback via H 3 receptors could contribute to increased signaling of H 1 receptors. Apoe -/-mice showed higher sensitivity to the anxiety-reducing effects of the H 1 receptor antagonist mepyramine than wild-type mice. These effects were dissociated from effects of mepyramine on the HPA axis. Compared to saline controls, mepyramine reduced plasma ACTH and corticosterone levels in wild-type, but not Apoe -/-, mice. These data support a role for apoE in H 3 receptor signaling. H 3 antagonists were proposed as a treatment for cognitive disorders such as Alzheimer's disease, which is associated with increased anxiety and cognitive impairments. As H 3 antagonists increase measures of anxiety and impair object recognition in wild-type mice, the use of H 3 antagonists in cognitive disorders may be counterproductive and should be carefully evaluated.

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“…In the auditory cortex an increase of dopaminergic activity evaluated by microdialysis appeared to reflect the initial formation of the behaviorally relevant association [120], and the phasic activation of mesocortical and mesolimbic dopaminergic systems is differentially influenced by associative and non associative learning mechanisms [11]. Histamine implications in learning and memory is supported by extensive experimental evidence [94,124], and there is evidence that histaminergic H 3 receptor antagonists facilitated memory acquisition [51], possibly through cholinergic mechanisms [99]. Interestingly the effect of tacrine (1,2,3,4-tetrahydroamino-9-acridinamine), which alleviates Alzheimer's disease symptoms in some patients, may be partly due to multiple pharmacological mechanisms.…”

Section: Introductionmentioning

confidence: 95%

“…The disruption of the cortical cholinergic system may account for the cognitive impairments, since reduced availability of ACh in the synaptic cleft appeared related to cognitive deficits [111]. The lack of effectiveness of the same doses of imetit and R-a-methylhistamine when administered post-training, suggests that the H 3 receptor is involved in the acquisition but not the recall of this information [51]. However, ACh may control both acquisition and retention processes, since also post-training administration of scopolamine resulted in animals exhibiting significantly shorter escape latencies during a passive avoidance response, and spending similar amount of tamine in learning and memory processes is highly probable, but at present experimental evidence appears to be inadequate to enable firm conclusions to be drawn on this role.…”

Section: Histamine and Cognitionmentioning

confidence: 99%

Interactions between histaminergic and cholinergic systems in learning and memory

Bacciottini

Passani

Mannaioni

et al. 2001

Behavioural Brain Research

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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.

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

Cited by 96 publications

References 43 publications

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

Interactions between histaminergic and cholinergic systems in learning and memory

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