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Role of histamine in attention and learning disorders
S.16 Histamine
in the bmin: focus on dementia and schizophrenia
this preparation, because HA neurons and their ascending projections are intact, while their descending projections and the ascending projections from the lower brainstem are largely (if not totally) interrupted, these data thus strongly support the importance of HArgic ascending projections in cortical arousal by demonstrating their ability to ensure cortical activation in the case of a deficit of the more caudal brainstem ascending activating systems. Among the widespread ascending outputs of HA cells, those projecting massively to the cholinergic basal forebrain could be of great importance since we have identified Ht-receptor mRNA in a large number of cholinergic neurons in this region (unpublished data). Furthermore, it has been shown that HA induces direct excitation of these corticalpetal cholinergic cells and increases significantly their discharge rate5. With respect to the descending projections of HA neurons and their role in cortical activation, on the other hand, we have found that these neurons send out also heavy inputs to the brainstem. Particularly, very dense axons are seen to reach the mesopontine tegmentum, which contains cholinergic neurons playing a key role in tonic cortical activation by their diencephalic projections2. Our double immunohistochemical studies further show that in this structure, HA axons form dense networks of very fine and vericose fibers and terminal-like dots in close proximity to a large number of cholinergic neurons and seem to make contact with them. Moreover, we have observed, by in situ hybridization coupled with immunocytochemistry of choline acethyhransferase in the guinea-pig, a strong expression of HI-receptor mRNA within cholinergic neurons in the mesopontine tegmentum (unpublished data). All these anatomical data suggest that the activity of mesopontine cholinergic neurons may be under a descending control of HA neurons. To verify this hypothesis and to explore the functional role of these HArgic descending inputs, we have further performed in situ pharmacological studies coupled with polygraphic recordings and spectral analysis of the cortical EEG in the cat. It is in the cholinergic mesopontine tegmentum that application of HA or a HI-receptor agonist by microdialysis disrupts cortical spindles and slow waves and enhances cortical fast rhythms, resulting in a long-lasting quiet waking state. The effects of HA are attenuated by systemic or in situ pretreatment with mepyramine, which, when injected alone, produces an increase in SWS’. Since in the mesopontine tegmentum, presumed cholinergic ascending neurons discharge tonically during cortical activation of W2, and since HA causes excitation of mesopontine cholinetgic neurons via HI-recepto&, we suggest that the HArgic descending afferents in the mesopontine tegmentum could promote cortical activation and W via, at least partially, activation of Ht -receptors situated on cholinergic neurons’. Taking together, these results indicate that 1) HA neurons constitute one of the major excitatory sources for cortical activation during waking and thus play an important role in brain arousal; that 2) the mechanisms involved include both their ascending and descending projections and implicate their interactions with other brain activating systems, particularly, choline& neurons and that 3) the close interactions between HArgic and cholinergic systems and the increase in cortical fast rhythms seen with ciproxifan suggest, in addition, a cognitive function for HArgic neurons. Refemnces [I] Lin et al, 1 Nemxci. 16, 1523-1537,1996 [Z] Sakai et al, In: The Diphencephalon & Sleep (Man& & Marini eds), p171198. Raven Press, 1990 [3] Haas, In: The histamine receptors (Schwartz & Haas eds), ~161-178, WileyLiss, 1992 [4] Ligneau et al, JPET, 287,658-666, 1998 [5] Khateb et al, Meurosci. 69, 495-506, 1995
@YKGl
iioz;J;istamine
in attention
and learning
J.L. Muir. School of Psychology. Card@ University, Wales, UK The role of the basal forebrain cholinergic system in cognitive and attentional functions has been the subject of considerable investigation
s173
following the suggestion that degeneration of this system may be responsible for many of the cognitive deficits associated with neurodegenerative diseases such as Alzheimer’s disease. Animal studies using a variety of behavioural tasks have investigated the role of the basal forebrain (BF) cholinergic system in cognitive and attentional function. Such studies (lesion and pharmacological) have also been conducted with a mind to investigating the feasibility of chohnergic replacement strategies. However, the effectiveness of such treatment for AD patients is limited by the fact that their cholinergic system is substantially compromised, thus reducing the availability of cholinergic neurons upon which to target such treatments. More recently, interest has developed in the potential of a novel therapeutic strategy for the treatment of cognitive dysfunction in the elderly and in Alzheimer’s disease patients, involving the use of histamine compounds. Unlike cholinergic neurons which are severely damaged in these patients, histaminergic neurons may be relatively spared and thus provide a means of cognitive enhancement via facilitation of histamine release from relatively intact neurons. Previous studies performed in mice using first generation H3-receptor antagonists, such as thioperamide, suggested enhancement of learning ability, e.g. in the Morris water maze. We have now assessed the H3-antagonist strategy in rata using Ciproxifan, a compound enhancing histamine release in brain with increased potency and have conducted initial studies using a second compound, which may be even more potent than Ciproxifan. The aim of the present series of studies was therefore to investigate the effect of administration of these novel H3-receptor antagonists on several behavioural paradigms used previously to assess the role of the cholinergic system or the effects of normal ageing on cognitive function. In these studies, impairments in the ability of rats to detect brief visual targets following cholinergic lesions were significantly improved following administration of the histaminergic compounds. In contrast, such compounds were ineffective in improving the short term memory deficit observed in normal animals on the delayed nomnatching-to-position task and had a limited effect in improving spatial learning in aged animals in the Morris water maze. Therefore, the results at the present time suggest that these histaminergic antagonists may have a role in enhancing attentional function.
-1
PET scan studies of histamlne human brain
receptors
in the
K. Yanai, T. Watanabe, M. Itoh’. Tohoku University School of Medicine, Department of Pharmacology, Sendai 980-85 75; I Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japan Histaminergic neurons are demonstrated in the rat brain. The cell bodies are located at posterior hypothalamus, and are shown to be involved in various physiological functions through H 1, H2, and H3 receptors. A role for brain histamine has long been thought to exist in arousal, sleep-wake cycle, appetite control, seizures, learning and memory, aggressive behaviors and emotion. These data were mainly obtained in rodents through classical pharmacological experiments and, recently, by the study of knockout mice. Positron emission tomography (PET) is a unique method to examine brain chemistry non-invasively in humans. We have been developing and utilizing the PET techniques to understand the functions of histaminergic neuronal system in the human brain. For histamine receptors, several radiotracers for selective labeling of Hl, H2, and H3 receptors have been synthesized. We have been utilizing two carbon11 labeled Hl-receptor ligands, [“C]pyrilamine and [“Cldoxepin for human PET studies (1). In this paper, we mainly describe the human PET studies of [“Cldoxepin. Three topics of our studies on Hl receptor imaging are as follows: the effects of normal and abnormal aging on Hi receptors, epilepsy and HI receptors, and Hl receptor occupancy by sedating and non-sedating antihistaminics. In control young subjects, a high density of Hl-receptors was observed in the cingulate gyms, frontal cortex, temporal cortex, and hippocampus. On the contrary, the cerebellum and pons have few Hl receptors. The Hl receptor binding in the cortex was significantly decreased with age (2). The frontal and temporal cortex showed age-dependent decrease in binding of approximately 12 percent per decade. Statistical parametric
in the bmin: focus on dementia and schizophrenia
this preparation, because HA neurons and their ascending projections are intact, while their descending projections and the ascending projections from the lower brainstem are largely (if not totally) interrupted, these data thus strongly support the importance of HArgic ascending projections in cortical arousal by demonstrating their ability to ensure cortical activation in the case of a deficit of the more caudal brainstem ascending activating systems. Among the widespread ascending outputs of HA cells, those projecting massively to the cholinergic basal forebrain could be of great importance since we have identified Ht-receptor mRNA in a large number of cholinergic neurons in this region (unpublished data). Furthermore, it has been shown that HA induces direct excitation of these corticalpetal cholinergic cells and increases significantly their discharge rate5. With respect to the descending projections of HA neurons and their role in cortical activation, on the other hand, we have found that these neurons send out also heavy inputs to the brainstem. Particularly, very dense axons are seen to reach the mesopontine tegmentum, which contains cholinergic neurons playing a key role in tonic cortical activation by their diencephalic projections2. Our double immunohistochemical studies further show that in this structure, HA axons form dense networks of very fine and vericose fibers and terminal-like dots in close proximity to a large number of cholinergic neurons and seem to make contact with them. Moreover, we have observed, by in situ hybridization coupled with immunocytochemistry of choline acethyhransferase in the guinea-pig, a strong expression of HI-receptor mRNA within cholinergic neurons in the mesopontine tegmentum (unpublished data). All these anatomical data suggest that the activity of mesopontine cholinergic neurons may be under a descending control of HA neurons. To verify this hypothesis and to explore the functional role of these HArgic descending inputs, we have further performed in situ pharmacological studies coupled with polygraphic recordings and spectral analysis of the cortical EEG in the cat. It is in the cholinergic mesopontine tegmentum that application of HA or a HI-receptor agonist by microdialysis disrupts cortical spindles and slow waves and enhances cortical fast rhythms, resulting in a long-lasting quiet waking state. The effects of HA are attenuated by systemic or in situ pretreatment with mepyramine, which, when injected alone, produces an increase in SWS’. Since in the mesopontine tegmentum, presumed cholinergic ascending neurons discharge tonically during cortical activation of W2, and since HA causes excitation of mesopontine cholinetgic neurons via HI-recepto&, we suggest that the HArgic descending afferents in the mesopontine tegmentum could promote cortical activation and W via, at least partially, activation of Ht -receptors situated on cholinergic neurons’. Taking together, these results indicate that 1) HA neurons constitute one of the major excitatory sources for cortical activation during waking and thus play an important role in brain arousal; that 2) the mechanisms involved include both their ascending and descending projections and implicate their interactions with other brain activating systems, particularly, choline& neurons and that 3) the close interactions between HArgic and cholinergic systems and the increase in cortical fast rhythms seen with ciproxifan suggest, in addition, a cognitive function for HArgic neurons. Refemnces [I] Lin et al, 1 Nemxci. 16, 1523-1537,1996 [Z] Sakai et al, In: The Diphencephalon & Sleep (Man& & Marini eds), p171198. Raven Press, 1990 [3] Haas, In: The histamine receptors (Schwartz & Haas eds), ~161-178, WileyLiss, 1992 [4] Ligneau et al, JPET, 287,658-666, 1998 [5] Khateb et al, Meurosci. 69, 495-506, 1995
@YKGl
iioz;J;istamine
in attention
and learning
J.L. Muir. School of Psychology. Card@ University, Wales, UK The role of the basal forebrain cholinergic system in cognitive and attentional functions has been the subject of considerable investigation
s173
following the suggestion that degeneration of this system may be responsible for many of the cognitive deficits associated with neurodegenerative diseases such as Alzheimer’s disease. Animal studies using a variety of behavioural tasks have investigated the role of the basal forebrain (BF) cholinergic system in cognitive and attentional function. Such studies (lesion and pharmacological) have also been conducted with a mind to investigating the feasibility of chohnergic replacement strategies. However, the effectiveness of such treatment for AD patients is limited by the fact that their cholinergic system is substantially compromised, thus reducing the availability of cholinergic neurons upon which to target such treatments. More recently, interest has developed in the potential of a novel therapeutic strategy for the treatment of cognitive dysfunction in the elderly and in Alzheimer’s disease patients, involving the use of histamine compounds. Unlike cholinergic neurons which are severely damaged in these patients, histaminergic neurons may be relatively spared and thus provide a means of cognitive enhancement via facilitation of histamine release from relatively intact neurons. Previous studies performed in mice using first generation H3-receptor antagonists, such as thioperamide, suggested enhancement of learning ability, e.g. in the Morris water maze. We have now assessed the H3-antagonist strategy in rata using Ciproxifan, a compound enhancing histamine release in brain with increased potency and have conducted initial studies using a second compound, which may be even more potent than Ciproxifan. The aim of the present series of studies was therefore to investigate the effect of administration of these novel H3-receptor antagonists on several behavioural paradigms used previously to assess the role of the cholinergic system or the effects of normal ageing on cognitive function. In these studies, impairments in the ability of rats to detect brief visual targets following cholinergic lesions were significantly improved following administration of the histaminergic compounds. In contrast, such compounds were ineffective in improving the short term memory deficit observed in normal animals on the delayed nomnatching-to-position task and had a limited effect in improving spatial learning in aged animals in the Morris water maze. Therefore, the results at the present time suggest that these histaminergic antagonists may have a role in enhancing attentional function.
-1
PET scan studies of histamlne human brain
receptors
in the
K. Yanai, T. Watanabe, M. Itoh’. Tohoku University School of Medicine, Department of Pharmacology, Sendai 980-85 75; I Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japan Histaminergic neurons are demonstrated in the rat brain. The cell bodies are located at posterior hypothalamus, and are shown to be involved in various physiological functions through H 1, H2, and H3 receptors. A role for brain histamine has long been thought to exist in arousal, sleep-wake cycle, appetite control, seizures, learning and memory, aggressive behaviors and emotion. These data were mainly obtained in rodents through classical pharmacological experiments and, recently, by the study of knockout mice. Positron emission tomography (PET) is a unique method to examine brain chemistry non-invasively in humans. We have been developing and utilizing the PET techniques to understand the functions of histaminergic neuronal system in the human brain. For histamine receptors, several radiotracers for selective labeling of Hl, H2, and H3 receptors have been synthesized. We have been utilizing two carbon11 labeled Hl-receptor ligands, [“C]pyrilamine and [“Cldoxepin for human PET studies (1). In this paper, we mainly describe the human PET studies of [“Cldoxepin. Three topics of our studies on Hl receptor imaging are as follows: the effects of normal and abnormal aging on Hi receptors, epilepsy and HI receptors, and Hl receptor occupancy by sedating and non-sedating antihistaminics. In control young subjects, a high density of Hl-receptors was observed in the cingulate gyms, frontal cortex, temporal cortex, and hippocampus. On the contrary, the cerebellum and pons have few Hl receptors. The Hl receptor binding in the cortex was significantly decreased with age (2). The frontal and temporal cortex showed age-dependent decrease in binding of approximately 12 percent per decade. Statistical parametric