Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms

Abstract. The aim of this study was to investigate the effects of histamine H 1 and H 3 antagonists on learning and mnemonic dysfunction in mice. Two H 1 antagonists, pyrilamine and clozapine, and the prototypic H 3 antagonist thioperamide were used to study the role of histamine in mice with social isolation and repeated methamphetamine administration. Mice with social isolation and repeated methamphetamine administration showed significant disruption of prepulse inhibition as compared to both the socially-housed mice and isolation-housing mice. Furthermore, social isolation and repeated methamphetamine administration caused significant learning and mnemonic dysfunctions. Treatment with clozapine improved learning and mnemonic ability in all of the tasks. Pyrilamine treatment ameliorated performance in all the tests examined except for the passive avoidance test. Thioperamide, however, did not change the learning and mnemonic ability. Donepezil, an acetylcholinesterase inhibitor, reversed the learning and mnemonic dysfunction in all four tasks. The present study has shown that blockade of histamine H 1 receptor improved the learning and mnemonic ability in mice, raising the possibility that treatment with clozapine or pyrilamine may improve learning and mnemonic performance in certain patients with psychiatric diseases such as schizophrenic patients with cognitive dysfunction.

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“…A significant increase in the level of N τ -methylhistamine was found in the cerebrospinal fluid of schizophrenics (22). A binding study using […”

Section: Discussionmentioning

confidence: 99%

Blocking Histamine H1 Improves Learning and Mnemonic Dysfunction in Mice With Social Isolation Plus Repeated Methamphetamine Injection

et al. 2008

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“…Twotailed comparisons of allele frequencies and genotype distributions were performed with 2 test except for 2 × 2 contingency tables for which Fisher exact test was used. 2 and P values were calculated using Instat for windows 95. In all cases, P values less than 0.05 were considered to be statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…In agreement, a recent study reported that levels of tele-methylhistamine, the major HA metabolite in brain, are enhanced in cerebrospinal fluid of schizophrenic patients, suggesting an increased activity of central HA neurons. 2 In contrast to 'typical' antipsychotics which tend to decrease HA neuron activity in vivo, 'atypical' neuroleptics markedly stimulate this activity, an effect that may underlie their therapeutic efficacy on negative symptoms of schizophrenia. 3 has also been observed in the frontal cortex of patients with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Histamine H2 receptor gene variants: lack of association with schizophrenia

et al. 2000

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A role of histaminergic neuronal systems in schizophrenia was suggested by an association with several polymorphisms located in the coding region of the histamine H 2 -receptor (H2R) gene (Orange et al, Mol Psychiatry 1996; 1: 466-469). Using either the reference method of direct sequencing or restriction endonuclease digestion of PCR products amplified from DNA, we could not confirm the existence of these polymorphisms in 53 Swedish controls, 52 French controls and 88 French schizophrenics. In contrast, we detected a G543A transition in the coding region of the gene that was not found in the British population. This allelic variation, which was observed in 15% of the controls with no homozygotes, did not change the amino acid sequence of the receptor. We also analyzed a 1.8-kb nucleotide sequence of the promoter region in which we detected two additional polymorphisms that may modulate the expression of the H2R gene. The first one was a A-592G transition located in the minimal promoter of the gene and found in ෂ10% of controls with no homozygotes. The second one was a G-1018A transition located in an enhancer element of the promoter and was found in ෂ20-30% of controls (with ෂ2-4% homozygotes). DNA analysis of the 88 French schizophrenic subjects revealed that the incidence of the three polymorphisms was not significantly different in this population. In conclusion, the present findings may suggest a surprisingly high variability of the H2R gene polymorphisms in different geographical areas but do not support an association of these allelic variations with schizophrenia. Molecular Psychiatry (2000) 5, 159-164.

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“…In mice, oral administration of BF2.649 caused a dose-dependent reduction of neocortical slow activity (at δ range 0.8-2.5 Hz) and spindles (8)(9)(10)(11)(12)(13)(14)(15) and an increase in power spectral density of neocortical fast rhythms (β and γ bands, mainly 30-60 Hz) resulting in a marked enhancement of cortical activation, i.e. low voltage and fast electrical activity with dominant waves in the β and γ bands (Fig.…”

Section: Effect Of Bf2649 On the Cortical Eeg And Sleep-wake Cycle Imentioning

confidence: 99%

“…Levels of t-MeHA are significantly elevated in the cerebrospinal fluid of patients with chronic schizophrenia [10] whereas H 1 receptor-mediated responses are blunted [11,12] and H 1 -receptor binding reduced in cortical areas of these patients [13], possibly reflecting a down-regulation of the receptor consequent to overstimulation by endogenous histamine.…”

Section: Introductionmentioning

confidence: 99%

Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

Ligneau

Landais

Perrin

et al. 2007

Biochemical Pharmacology

103

104

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BF2.649, a high affinity and selective non-imidazole histamine H 3 -receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C max or AUC values. At low oral doses (2.5-20 mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation.DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons.BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition.These observations suggest that H 3 -receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.

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Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms

Cited by 115 publications

References 64 publications

Blocking Histamine H1 Improves Learning and Mnemonic Dysfunction in Mice With Social Isolation Plus Repeated Methamphetamine Injection

Blocking Histamine H1 Improves Learning and Mnemonic Dysfunction in Mice With Social Isolation Plus Repeated Methamphetamine Injection

Histamine H2 receptor gene variants: lack of association with schizophrenia

Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

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