Excitatory effect of histamine on the arousal system

  • Kenji Tasaka


It has been reported that histamine appears to act as a neurotransmitter in the mammalian brain (Schwartz, 1975). In 1954, Feldberg and Sherwood demonstrated that intracerebroventricular (i.c.v.) injection of histamine (200 μg) elicited a decrease in spontaneous activity and sleepiness in cats. In mice and rats, it was also found that high doses of histamine (i.c. v., 20–100 μg) produced sedation, ptosis and drowsy patterns in spontaneous EEGs characterized by high amplitude and low frequency EEG waves (Kamei et al., 1981). Moreover, i.c.v. injection of histamine (at doses of μg or more) elicited an inhibition of the pinna reflex (Kamei et al., 1984) as well as a prolongation of thiopental sleeping time in mice (Kamei et al., 1986). These findings seem to suggest that high doses of histamine exerts an inhibitory influence on the central nervous system (CNS). By contrast, Monnier et al. (1970, 1977) reported that intravenous (i.v.) and i.c.v. injection of histamine induced an EEG arousal response characterized by decreased delta activity in the cerebral cortex. It has also been shown that histamine (250 ng) induced a significant increase in spontaneous motor activity in the conscious rat, including increased grooming and exploratory behavior, indicating that histamine may be involved in modulating behavioral arousal (Kalivas, 1982). In accordance with this view, H1 antagonists have caused drowsy patterns in spontaneous EEGs and sedative effects in humans (Carruthers et al., 1978) and experimental animals (Heinrich, 1953; Tasaka et al., 1986)


Electrical Stimulation Arousal Effect Spontaneous Motor Activity Histamine Content Delta Wave 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arduini, A.: Enduring potential changes evoked in the cerebral cortex by stimulation of brainstem reticular formation and thalamus. In: Jasper, H.H. et al., (ed) Reticular formation of the brain. Boston: Little· Brown and Co., pp. 333–351, 1958Google Scholar
  2. Arrang, J.-M., Garbarg, M. and Schwartz, J.-C.: Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature, 302, 832–837 (1983)PubMedCrossRefGoogle Scholar
  3. Arrang, J.-M., Garbarg, M. and Schwartz, J.-C.: Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors. Neuroscience, 23, 149–157 (1987)PubMedCrossRefGoogle Scholar
  4. Carruthers, S.G., Shoeman, D.W., Hignite, C.E. and Azarnoff, D.L.: Correlation between plasma diphenhydramine level and sedative and antihistamine effects. Clin. Pharmacol. Ther., 23, 375–382 (1978)PubMedGoogle Scholar
  5. Cooley, J.W. and Tukey, J.W.: An algorithm for the machine calculation of complex Fourier series. Math. Comput, 19, 297–301 (1965)CrossRefGoogle Scholar
  6. Douglas, W.W.: Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In: Gilman, A.G., Goodman, L.S., Rall, T.W., Murad, F. (ed) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 7th ed. New York, Macmillan Publishing Co., pp. 605–638, 1985Google Scholar
  7. Favale, E., Loeb, C., Rossi, G.F. and Sacco, G.: EEG synchronization and behavioral signs of sleep following low frequency stimulation of the brain stem reticular formation. Acta. Ital. Biol., 99, 1–22 (1961)Google Scholar
  8. Feldberg, W. and Sherwood, S.L.: Injections of drugs into the lateral ventricle of the cat J. Physiol., 123, 148–167 (1954)PubMedGoogle Scholar
  9. Garbarg, M., Trung Tuong, M.D., Gros, C. and Schwartz, J.C.: Effects of histamine H3-receptor ligands on various biochemical indices of histaminergic neuron activity in rat brain. European J. Pharmacol., 164, 1–11 (1989)Google Scholar
  10. Heinrich, M.A. Jr.: The effects of antihistaminic drugs on the central nervous system in rats and mice. Arch. int. Pharmacodyn., 92, 446–463 (1953)Google Scholar
  11. Jasper, H.: Diffuse projection systems: The integrative action of the thalamic reticular system. EEG Clin. Neurophysiol., 1, 405–420 (1949)Google Scholar
  12. Jones, B.E. and Yang, T.-Z.: The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J. Comp. Neurol., 242, 56–92 (1985)PubMedCrossRefGoogle Scholar
  13. Kalivas, P.W.: Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. J. Pharmacol. Exp. Ther., 222, 37–42 (1982)PubMedGoogle Scholar
  14. Kamei, C., Chung, Y.H., Dabasaki, T. and Tasaka, K: Species differences elicited by intraventricular injection of histamine on EEGs and behavior. Japan. J. Pharmacol., 31 (suppl), 86p (1981)CrossRefGoogle Scholar
  15. Kamei, C., Dabasaki, T. and Tasaka, K: Effect of intraventricular injection of histamine on the pinna reflex in mice. Japan. J. Pharmacol., 35, 193–195 (1984)Google Scholar
  16. Kamei, C., Akahori, H. and T asaka, K: Influence of histamine and related compounds on the hypnotic effect of thiopental in mice. J. Pharmacobio-Dyn., 9, 112–116 (1986)PubMedCrossRefGoogle Scholar
  17. Kamei, C., Okumura, Y. and Tasaka, K: Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology, 111, 376–382 (1993).PubMedCrossRefGoogle Scholar
  18. Lin, J.-S., Sakai, K, Vanni-Mercier, G., Arrang, J.-M., Garbarg, M., Schwartz, J.-C. and Jouvet, M.: Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat. Brain Res., 523, 325–330 (1990)PubMedCrossRefGoogle Scholar
  19. Mancia, M., Avanzini, G., Caccia, M. and Rocca, E.: Recruiting responses following splitting of the brain-stem in cats. EEG Clin. Neurophysiol., 31, 259–268 (1971)Google Scholar
  20. Menétrey, D.: Retrograde tracing of neural pathways with a protein-gold complex. I. Light microscopic detection after silver intensification. Histochemistry, 83, 391–395 (1985)PubMedCrossRefGoogle Scholar
  21. Monnier, M., Sauer, R. and Hatt, A.M.: The activating effect of histamine on the central nervous system. Int. Rev. Neurobiol., 12, 265–305 (1970)PubMedCrossRefGoogle Scholar
  22. Monnier, M. and Herkert, B.: Variations of histamine concentration in sleep and arousal hemodialysates (seasonal, thalamic and reticular influences). Arch. int. Pharmacodyn., 228, 39–49 (1977)Google Scholar
  23. Moruzzi, G. and Magoun, H.W.: Brain stem reticular formation and activation of the EEG. EEG Clin. Neurophysiol., 1, 455–473 (1949)Google Scholar
  24. Nakano, K, Kohno, M., Hasegawa, Y. and Tokushige, A.: Cortical and brain stem afferents to the ventral thalamic nuclei of the cat demonstrated by retrograde axonal transport of horseradish peroxidase. J. Comp. Neurol., 231, 102–120 (1985)PubMedCrossRefGoogle Scholar
  25. Oishi, R., Itoh, Y., Nishibori, M. and Saeki, K: Effects of the histamine H3-agonist (R)-α-methylhistamine and the antagonist thioperamide on histamine metabolism in the mouse and rat brain. J. Neurochem., 52, 1388–1392 (1989)PubMedCrossRefGoogle Scholar
  26. Purpura, D.P., Shofer, R.J. and Musgrave, F.S.: Cortical intracellular potentials during augmenting and recruiting responses. II. Patterns of synaptic activities in pyramidal and nonpyramidal tract neurons. J. Neurophysiol., 27, 133–151 (1964)PubMedGoogle Scholar
  27. Rossi, G.F.: Brain stem facilitating influences on EEG synchronization. Experimental findings and observations in man. Acta Neurochir., 13, 257–288 (1965)CrossRefGoogle Scholar
  28. Sakai, N., Sakurai, A., Sakurai, E., Yanai, K, Maeyama, K and Watanabe, T.: Effects. of the histamine H3 receptor ligands thioperamide and (R)-α-methylhistamine on histidine decarboxylase activity of mouse brain. Biochem. Biophys. Res. Commun., 185, 121–126 (1992)PubMedCrossRefGoogle Scholar
  29. Schwartz, J.C., Lampart, C. and Rose, C.: Histamine formation in rat brain in vivo: Effects of histidine loads. J. Neurochem., 19, 801–810 (1972)PubMedCrossRefGoogle Scholar
  30. Schwartz, J.-C.: Histamine as a transmitter in brain. Life Sci., 17, 503–518 (1975)PubMedCrossRefGoogle Scholar
  31. Tasaka, M., Kojima, H. and Akashi, A: An electroencephalographical study on timiperone, a new antipsychotic drug. Folia pharmacol. japon., 84, 213–219 (1984)CrossRefGoogle Scholar
  32. Tasaka, K., Kamei, C., Katayama, S., Kitazumi, K., Akahori, H. and Hokonohara, T.: Comparative study of various H1-blockers on neuropharmacological and behavioral effects including 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl) benzimidazole difumarate (KB-2413), a new antiallergic agent. Arch. int. Pharmacodyn., 280, 275–291 (1986)Google Scholar
  33. Tasaka, K., Chung, Y.H., Sawada, K. and Mio, M.: Excitatory effect of histamine on the arousal system and its inhibition by H1 blockers. Brain Res. Bull., 22, 271–275 (1989)PubMedCrossRefGoogle Scholar
  34. Tasaka, K., Chung, Y.H., Mio, M. and Kamei, C.: The pathway responsible for EEG synchronization and effect of histamine on this system. Brain Res. Bull., 32, 365–371 (1993)PubMedCrossRefGoogle Scholar
  35. Velayos, J.L. and Reinoso-Suarez, F.: Topographic organization of the brainstem afferents to the mediodorsal thalamic nucleus. J. Compo Neurol., 206, 17–27 (1982)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1994

Authors and Affiliations

  • Kenji Tasaka
    • 1
  1. 1.The Department of Pharmacology in the Faculty of Pharmaceutical SciencesOkayama UniversityOkayamaJapan

Personalised recommendations