Histaminergic systems and sleep: studies in man with HI and H2 antagonists

doi:10.1016/0028-3908(85)90081-4

Neuropharmacology

Volume 24, Issue 3, March 1985, Pages 245-250

https://doi.org/10.1016/0028-3908(85)90081-4 Get rights and content

Abstract

Effects of H1 (mepyramine, mequitazine, triprolidine and brompheniramine) and H2 (cimetidine and ranitidine) antagonists on sleep were studied in healthy man. There were no effects of mepyramine (50 and 100mg), and the only effect of mequitazine (5 and 10mg) was a reduction in the number of awakenings. Triprolidine (10 and 20 mg) and brompheniramine (4 and 8mg) did not alter wakefulness during sleep or the total sleep time, but rapid eye movement sleep was reduced. There were no effects of ranitidine (150 and 300 mg), but slow wave sleep was increased by cimetidine (200 and 400 mg). It is tentatively suggested that the histaminergic system is concerned with the mechanisms which favour vigilance during the wakeful state, and the balance between wakefulness and slow wave activity during sleep. Effects of some H1 antihistamines on rapid eye movement sleep are believed to be due to their monoaminergic rather than their histaminergic activity.

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Insomnia represents a significant public health burden worldwide. Antidepressants have often been the insomnia treatment of choice in recent decades. Some tricyclic antidepressants (TCAs) have been shown to improve sleep efficiency.
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Relevant studies were identified in electronic databases such as PubMed, Cochrane, Embase, and Web of Science, up until July 2016. We included all polysomnographic (PSG) RCTs using TCAs to treat insomnia. The primary outcome measure was the total sleep time (TST), although other polysomnographic measures were also investigated. Next-day somnolence and dropout rates were also assessed.
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Based on our limited data analysis with two medications at particular doses (most studies included extremely low doxepin), we assert that TCAs can be an effective pharmacological treatment for insomnia. TCAs were found to improve sleep outcome measures, with the notable exception of an 82% increase in somnolence. Overall TCAs have very problematic and dangerous side effects, while TCAs were not found to increase the dropout rate compared with the placebo.
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For example, hibernation is distinct from sleep in that reversibility to the alert state is not rapid. Furthermore, the application of these definitions to simple animal models led to intriguing findings that several genetic components related to sleep are conserved across different species, including salt-induced kinase 3 (SIK3) (Funato et al., 2016), epidermal growth factor signaling pathway (Foltenyi et al., 2007; Kramer et al., 2003, 2001; Kushikata et al., 1998; Van Buskirk and Sternberg, 2007), protein kinase G (Langmesser et al., 2009; Raizen et al., 2008), cyclic adenosine monophosphate signaling pathway (Graves, 2003; Hendricks et al., 2001; Raizen et al., 2008), dopaminergic pathway (Singh et al., 2014; Wisor et al., 2001), histaminergic pathway (Haas et al., 2008; Monnier et al., 1967; Nicholson et al., 1985; Oh et al., 2013; Renier et al., 2007; Sundvik et al., 2011), and N-methyl-d-aspartate (NMDA) receptors (Sunagawa et al., 2016; Tomita et al., 2015). Cautious interpretation is necessary, however, as many of these pathways, proteins, and neurotransmitters are involved in a variety of cellular events, and not specifically in sleep.
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The neurotransmitter histamine has been suggested to be involved in cognitive functioning. Generally, studies in animals have shown a decrease in performance after decreasing histamine neurotransmission and improved performance after increasing histamine neurotransmission. It is unclear, however, what role histamine plays in cognition in humans. Up until now, most data are derived from studies and reviews that aimed to assess the sedative potential of H₁-antagonists and not the effects on cognition in particular. The objective of this paper is specifically to review which cognitive domains are affected by H₁-antagonists. Taken together, 90 experimental studies on the performance effects of sedative H₁-antagonists published between 1973 and 2009 were reviewed. Results showed that psychomotor skills and attention are most frequently impaired and memory the least. Tasks assessing memory that were affected usually required rapid responses. It was concluded that both the complexity of the task as well as the demand for information processing speed determines the sensitivity to the effects of central H₁-antagonism. The importance of the sensitive cognitive domains to histaminergic dysfunction, as well as the relation between histamine related decrease in arousal and task performance deserve further research.
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Increased activity of the histaminergic neurons of the posterior hypothalamus has been implicated in the facilitation of behavioral wakefulness. Recent evidence of reciprocal projections between the sleep-active neurons of the preoptic/anterior hypothalamus and the histaminergic neurons of the tuberomammillary nucleus suggests that histaminergic innervation of the preoptic/anterior hypothalamic area may be of particular importance in the wakefulness-promoting properties of histamine. To test this possibility, we used microdialysis sample collection in the preoptic/anterior hypothalamic area of cats during natural sleep–wakefulness cycles, 6 h of sleep deprivation induced by gentle handling/playing, and recovery sleep. Samples were analyzed by a sensitive radioenzymatic assay. Mean basal levels of histamine in microdialysate during periods of wakefulness (1.155±0.225 pg/μl) did not vary during the 6 h of sleep deprivation. However, during the different sleep states, dramatic changes were observed in the extracellular histamine levels of preoptic/anterior hypothalamic area: wakefulness>non-rapid eye movement sleep>rapid eye movement sleep. Levels of histamine during rapid eye movement sleep were lowest (0.245±0.032 pg/μl), being significantly lower than levels during non-rapid eye movement sleep (0.395±0.081 pg/μl) and being only 21% of wakefulness levels.
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Neuropharmacology

Abstract

References (31)

Histamine H1 receptors in human brain labelled with [³H]doxepin

Brain Res.

Antihistamines and sedation

Lancet

in vivo occupation of cerebral histamine Hl-receptors evaluated with ³H-mepyramine may predict sedative properties of psychotropic drug

Eur. J. Pharmac.

Histamine receptors in the brain and their possible functions

Distribution of the histaminergic neuron system in the central nervous system of rats: A flourescent immunohistochemical analysis with histidine decarboxylase as a marker

Brain Res.

Examination of residuals

An analysis of transformations

J. R. statist. Soc.

Histamine potentiates the effects of excitatory amino acids on quiescent neurones in the rat medulla

Br. J. Pharmac.

Effects on the central nervous system of two isomers of ephedrine and triprolidine, and their interactions

Br. J. clin. Pharmac.

Performance studies with antihistamines

Br. J. clin. Pharmac.

New tests for multiple comparisons with a control

Biometrics

Recent developments in brain histamine research: pathways and receptors

Essai compare d'un nouvel antihistaminique, la mequitazine et d'un placebo

Acta allerg.

Affinities of histamine H1-antagonists in guinea-pig brain: Similarity of values determined from [³H]mepyramine binding and from inhibition of a functional response

J. Neurochem.

Effects of tricyclic compounds on the histamine response of isolated atria

J. Pharmac. exp. Ther.

Cited by (87)

Treatment of insomnia with tricyclic antidepressants: a meta-analysis of polysomnographic randomized controlled trials

Sleep in vertebrate and invertebrate animals, and insights into the function and evolution of sleep

Cognitive domains affected by histamine H<inf>1</inf>-antagonism in humans: A literature review

Sleep Pharmacology

Extracellular histamine levels in the feline preoptic/anterior hypothalamic area during natural sleep-wakefulness and prolonged wakefulness: An in vivo microdialysis study

Efficacy of Triprolidine in the Treatment of Temporary Sleep Disturbance

Histaminergic systems and sleep: studies in man with HI and H2 antagonists

Abstract

Brain Res.

Lancet

Eur. J. Pharmac.

Brain Res.

Examination of residuals

An analysis of transformations

J. R. statist. Soc.

Histamine potentiates the effects of excitatory amino acids on quiescent neurones in the rat medulla

Br. J. Pharmac.

Effects on the central nervous system of two isomers of ephedrine and triprolidine, and their interactions

Br. J. clin. Pharmac.

Performance studies with antihistamines

Br. J. clin. Pharmac.

New tests for multiple comparisons with a control

Biometrics

Recent developments in brain histamine research: pathways and receptors

Essai compare d'un nouvel antihistaminique, la mequitazine et d'un placebo

Acta allerg.

Affinities of histamine H1-antagonists in guinea-pig brain: Similarity of values determined from [3H]mepyramine binding and from inhibition of a functional response

J. Neurochem.

Effects of tricyclic compounds on the histamine response of isolated atria

J. Pharmac. exp. Ther.

Affinities of histamine H1-antagonists in guinea-pig brain: Similarity of values determined from [³H]mepyramine binding and from inhibition of a functional response