Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Dec;119(8):1656–1664. doi: 10.1111/j.1476-5381.1996.tb16086.x

Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats.

P Blandina 1, M Giorgetti 1, L Bartolini 1, M Cecchi 1, H Timmerman 1, R Leurs 1, G Pepeu 1, M G Giovannini 1
PMCID: PMC1915786  PMID: 8982515

Abstract

1. The effects of histamine and agents at histamine receptors on spontaneous and 100 mM K(+)-evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving, rats, and on cognitive tests are described. 2. Local administration of histamine (0.1-100 microM) failed to affect spontaneous but inhibited 100 mM K(+)-stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)-alpha-methylhistamine (RAMH) (0.1-10 microM), imetit (0.01-10 microM) and immepip (0.01-10 microM) mimicked the effect of histamine. 3. Neither 2-thiazolylethylamine (TEA), an agonist showing some selectivity for H1 receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K(+)-evoked release of acetylcholine. 4. The inhibitory effect of 100 microM histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H1 and H2 but not H3 receptors. 5. The H3 receptor-induced inhibition of K(+)-evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX). 6. The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg-1) and RAMH (5 mg kg-1) were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K(+)-evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response. 7. These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Full text

PDF
1656

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arrang J. M., Drutel G., Schwartz J. C. Characterization of histamine H3 receptors regulating acetylcholine release in rat entorhinal cortex. Br J Pharmacol. 1995 Apr;114(7):1518–1522. doi: 10.1111/j.1476-5381.1995.tb13379.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arrang J. M., Garbarg M., Lancelot J. C., Lecomte J. M., Pollard H., Robba M., Schunack W., Schwartz J. C. Highly potent and selective ligands for histamine H3-receptors. Nature. 1987 May 14;327(6118):117–123. doi: 10.1038/327117a0. [DOI] [PubMed] [Google Scholar]
  3. Arrang J. M., Garbarg M., Schwartz J. C. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature. 1983 Apr 28;302(5911):832–837. doi: 10.1038/302832a0. [DOI] [PubMed] [Google Scholar]
  4. Arrang J. M., Garbarg M., Schwartz J. C. Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors. Neuroscience. 1987 Oct;23(1):149–157. doi: 10.1016/0306-4522(87)90279-x. [DOI] [PubMed] [Google Scholar]
  5. Ash A. S., Schild H. O. Receptors mediating some actions of histamine. Br J Pharmacol Chemother. 1966 Aug;27(2):427–439. doi: 10.1111/j.1476-5381.1966.tb01674.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beani L., Bianchi C., Giacomelli A., Tamberi F. Noradrenaline inhibition of acetylcholine release from guinea-pig brain. Eur J Pharmacol. 1978 Mar 15;48(2):179–193. doi: 10.1016/0014-2999(78)90327-8. [DOI] [PubMed] [Google Scholar]
  7. Black J. W., Duncan W. A., Durant C. J., Ganellin C. R., Parsons E. M. Definition and antagonism of histamine H 2 -receptors. Nature. 1972 Apr 21;236(5347):385–390. doi: 10.1038/236385a0. [DOI] [PubMed] [Google Scholar]
  8. Blandina P., Giorgetti M., Cecchi M., Leurs R., Timmerman H., Giovannini M. G. Histamine H3 receptor inhibition of K(+)-evoked release of acetylcholine from rat cortex in vivo. Inflamm Res. 1996 Mar;45 (Suppl 1):S54–S55. doi: 10.1007/BF03354086. [DOI] [PubMed] [Google Scholar]
  9. Blandina P., Knott P. J., Leung L. K., Green J. P. Stimulation of histamine H2 receptor in rat hypothalamus releases endogenous norepinephrine. J Pharmacol Exp Ther. 1989 Apr;249(1):44–51. [PubMed] [Google Scholar]
  10. Cacabelos R., Alvarez X. A. Histidine decarboxylase inhibition induced by alpha-fluoromethylhistidine provokes learning-related hypokinetic activity. Agents Actions. 1991 May;33(1-2):131–134. doi: 10.1007/BF01993147. [DOI] [PubMed] [Google Scholar]
  11. Clapham J., Kilpatrick G. J. Histamine H3 receptors modulate the release of [3H]-acetylcholine from slices of rat entorhinal cortex: evidence for the possible existence of H3 receptor subtypes. Br J Pharmacol. 1992 Dec;107(4):919–923. doi: 10.1111/j.1476-5381.1992.tb13386.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Clapham J., Kilpatrick G. J. Thioperamide, the selective histamine H3 receptor antagonist, attenuates stimulant-induced locomotor activity in the mouse. Eur J Pharmacol. 1994 Jul 1;259(2):107–114. doi: 10.1016/0014-2999(94)90498-7. [DOI] [PubMed] [Google Scholar]
  13. Cohen B. M., Renshaw P. F., Stoll A. L., Wurtman R. J., Yurgelun-Todd D., Babb S. M. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA. 1995 Sep 20;274(11):902–907. [PubMed] [Google Scholar]
  14. Cumming P., Shaw C., Vincent S. R. High affinity histamine binding site is the H3 receptor: characterization and autoradiographic localization in rat brain. Synapse. 1991 Jun;8(2):144–151. doi: 10.1002/syn.890080208. [DOI] [PubMed] [Google Scholar]
  15. Decker M. W., McGaugh J. L. The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory. Synapse. 1991 Feb;7(2):151–168. doi: 10.1002/syn.890070209. [DOI] [PubMed] [Google Scholar]
  16. Durant G. J., Emmett J. C., Ganellin C. R., Miles P. D., Parsons M. E., Prain H. D., White G. R. Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. J Med Chem. 1977 Jul;20(7):901–906. doi: 10.1021/jm00217a007. [DOI] [PubMed] [Google Scholar]
  17. Ennaceur A., Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988 Nov 1;31(1):47–59. doi: 10.1016/0166-4328(88)90157-x. [DOI] [PubMed] [Google Scholar]
  18. Ennaceur A., Meliani K. Effects of physostigmine and scopolamine on rats' performances in object-recognition and radial-maze tests. Psychopharmacology (Berl) 1992;109(3):321–330. doi: 10.1007/BF02245880. [DOI] [PubMed] [Google Scholar]
  19. GREEN J. P. HISTAMINE AND THE NERVOUS SYSTEM. Fed Proc. 1964 Sep-Oct;23:1095–1102. [PubMed] [Google Scholar]
  20. Garbarg M., Arrang J. M., Rouleau A., Ligneau X., Tuong M. D., Schwartz J. C., Ganellin C. R. S-[2-(4-imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist. J Pharmacol Exp Ther. 1992 Oct;263(1):304–310. [PubMed] [Google Scholar]
  21. Giovannini M. G., Mutolo D., Bianchi L., Michelassi A., Pepeu G. NMDA receptor antagonists decrease GABA outflow from the septum and increase acetylcholine outflow from the hippocampus: a microdialysis study. J Neurosci. 1994 Mar;14(3 Pt 1):1358–1365. doi: 10.1523/JNEUROSCI.14-03-01358.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Haroutunian V., Barnes E., Davis K. L. Cholinergic modulation of memory in rats. Psychopharmacology (Berl) 1985;87(3):266–271. doi: 10.1007/BF00432705. [DOI] [PubMed] [Google Scholar]
  23. Hough L. B. Cellular localization and possible functions for brain histamine: recent progress. Prog Neurobiol. 1988;30(6):469–505. doi: 10.1016/0301-0082(88)90032-9. [DOI] [PubMed] [Google Scholar]
  24. Ison R. R., Casy A. F. Structural influences upon antihistamine activity; 3-amino-1-aryl-1-(2-pyridyl)propenes and related compounds. J Pharm Pharmacol. 1971 Nov;23(11):848–856. doi: 10.1111/j.2042-7158.1971.tb10202.x. [DOI] [PubMed] [Google Scholar]
  25. Kamei C., Okumura Y., Tasaka K. Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology (Berl) 1993;111(3):376–382. doi: 10.1007/BF02244955. [DOI] [PubMed] [Google Scholar]
  26. Kamei C., Tasaka K. Participation of histamine in the step-through active avoidance response and its inhibition by H1-blockers. Jpn J Pharmacol. 1991 Dec;57(4):473–482. doi: 10.1254/jjp.57.473. [DOI] [PubMed] [Google Scholar]
  27. Kathmann M., Schlicker E., Detzner M., Timmerman H. Nordimaprit, homodimaprit, clobenpropit and imetit: affinities for H3 binding sites and potencies in a functional H3 receptor model. Naunyn Schmiedebergs Arch Pharmacol. 1993 Nov;348(5):498–503. doi: 10.1007/BF00173209. [DOI] [PubMed] [Google Scholar]
  28. Khateb A., Fort P., Pegna A., Jones B. E., Mühlethaler M. Cholinergic nucleus basalis neurons are excited by histamine in vitro. Neuroscience. 1995 Nov;69(2):495–506. doi: 10.1016/0306-4522(95)00264-j. [DOI] [PubMed] [Google Scholar]
  29. Klapdor K., Hasenöhrl R. U., Huston J. P. Facilitation of learning in adult and aged rats following bilateral lesions of the tuberomammillary nucleus region. Behav Brain Res. 1994 Mar 31;61(1):113–116. doi: 10.1016/0166-4328(94)90016-7. [DOI] [PubMed] [Google Scholar]
  30. Martinez-Mir M. I., Pollard H., Moreau J., Arrang J. M., Ruat M., Traiffort E., Schwartz J. C., Palacios J. M. Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res. 1990 Sep 3;526(2):322–327. doi: 10.1016/0006-8993(90)91240-h. [DOI] [PubMed] [Google Scholar]
  31. Meguro K., Yanai K., Sakai N., Sakurai E., Maeyama K., Sasaki H., Watanabe T. Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice. Pharmacol Biochem Behav. 1995 Mar;50(3):321–325. doi: 10.1016/0091-3057(95)00248-u. [DOI] [PubMed] [Google Scholar]
  32. Miyazaki S., Imaizumi M., Onodera K. Effects of thioperamide on the cholinergic system and the step-through passive avoidance test in mice. Methods Find Exp Clin Pharmacol. 1995 Dec;17(10):653–658. [PubMed] [Google Scholar]
  33. Mochizuki T., Okakura-Mochizuki K., Horii A., Yamamoto Y., Yamatodani A. Histaminergic modulation of hippocampal acetylcholine release in vivo. J Neurochem. 1994 Jun;62(6):2275–2282. doi: 10.1046/j.1471-4159.1994.62062275.x. [DOI] [PubMed] [Google Scholar]
  34. Morris R. G., Garrud P., Rawlins J. N., O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982 Jun 24;297(5868):681–683. doi: 10.1038/297681a0. [DOI] [PubMed] [Google Scholar]
  35. Oishi R., Nishibori M., Itoh Y., Shishido S., Saeki K. Is monoamine turnover in the brain regulated by histamine H3 receptors? Eur J Pharmacol. 1990 Aug 2;184(1):135–142. doi: 10.1016/0014-2999(90)90674-u. [DOI] [PubMed] [Google Scholar]
  36. Onodera K., Tuomisto L., Tacke U., Airaksinen M. Strain differences in regional brain histamine levels between genetically epilepsy-prone and resistant rats. Methods Find Exp Clin Pharmacol. 1992 Jan-Feb;14(1):13–16. [PubMed] [Google Scholar]
  37. Panula P., Pirvola U., Auvinen S., Airaksinen M. S. Histamine-immunoreactive nerve fibers in the rat brain. Neuroscience. 1989;28(3):585–610. doi: 10.1016/0306-4522(89)90007-9. [DOI] [PubMed] [Google Scholar]
  38. Parsons M. E., Owen D. A., Ganellin C. R., Durant G. J. Dimaprit -(S-[3-(N,N-dimethylamino)prophyl]isothiourea) - a highly specific histamine H2 -receptor agonist. Part 1. Pharmacology. Agents Actions. 1977 Mar;7(1):31–37. doi: 10.1007/BF01964878. [DOI] [PubMed] [Google Scholar]
  39. Petrides M. Frontal lobes and behaviour. Curr Opin Neurobiol. 1994 Apr;4(2):207–211. doi: 10.1016/0959-4388(94)90074-4. [DOI] [PubMed] [Google Scholar]
  40. Pollard H., Moreau J., Arrang J. M., Schwartz J. C. A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience. 1993 Jan;52(1):169–189. doi: 10.1016/0306-4522(93)90191-h. [DOI] [PubMed] [Google Scholar]
  41. Prell G. D., Green J. P. Histamine as a neuroregulator. Annu Rev Neurosci. 1986;9:209–254. doi: 10.1146/annurev.ne.09.030186.001233. [DOI] [PubMed] [Google Scholar]
  42. Prell G. D., Khandelwal J. K., Burns R. S., LeWitt P. A., Green J. P. Elevated levels of histamine metabolites in cerebrospinal fluid of aging, healthy humans. Compr Gerontol A. 1988 Oct;2(3):114–119. [PubMed] [Google Scholar]
  43. Prell G. D., Khandelwal J. K., Burns R. S., LeWitt P. A., Green J. P. Influence of age and gender on the levels of histamine metabolites and pros-methylimidazoleacetic acid in human cerebrospinal fluid. Arch Gerontol Geriatr. 1991 Jan-Feb;12(1):1–12. doi: 10.1016/0167-4943(91)90002-8. [DOI] [PubMed] [Google Scholar]
  44. Quirion R., Wilson A., Rowe W., Aubert I., Richard J., Doods H., Parent A., White N., Meaney M. J. Facilitation of acetylcholine release and cognitive performance by an M(2)-muscarinic receptor antagonist in aged memory-impaired. J Neurosci. 1995 Feb;15(2):1455–1462. doi: 10.1523/JNEUROSCI.15-02-01455.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sakai N., Yamazaki S., Onodera K., Yanai K., Maeyama K., Watanabe T. Effects of (S)-alpha-fluoromethylhistidine and (R)-alpha-methylhistamine on locomotion of W/Wv mice. Pharmacol Biochem Behav. 1993 Sep;46(1):95–99. doi: 10.1016/0091-3057(93)90323-l. [DOI] [PubMed] [Google Scholar]
  46. Schlicker E., Betz R., Göthert M. Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol. 1988 May;337(5):588–590. doi: 10.1007/BF00182737. [DOI] [PubMed] [Google Scholar]
  47. Schlicker E., Fink K., Detzner M., Göthert M. Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. J Neural Transm Gen Sect. 1993;93(1):1–10. doi: 10.1007/BF01244933. [DOI] [PubMed] [Google Scholar]
  48. Schlicker E., Fink K., Hinterthaner M., Göthert M. Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors. Naunyn Schmiedebergs Arch Pharmacol. 1989 Dec;340(6):633–638. doi: 10.1007/BF00717738. [DOI] [PubMed] [Google Scholar]
  49. Schwartz J. C., Arrang J. M., Garbarg M., Pollard H., Ruat M. Histaminergic transmission in the mammalian brain. Physiol Rev. 1991 Jan;71(1):1–51. doi: 10.1152/physrev.1991.71.1.1. [DOI] [PubMed] [Google Scholar]
  50. Smith C. P., Hunter A. J., Bennett G. W. Effects of (R)-alpha-methylhistamine and scopolamine on spatial learning in the rat assessed using a water maze. Psychopharmacology (Berl) 1994 May;114(4):651–656. doi: 10.1007/BF02244997. [DOI] [PubMed] [Google Scholar]
  51. Spignoli G., Pepeu G. Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine. Pharmacol Biochem Behav. 1987 Jul;27(3):491–495. doi: 10.1016/0091-3057(87)90353-4. [DOI] [PubMed] [Google Scholar]
  52. Sutherland R. J., Whishaw I. Q., Kolb B. A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat. Behav Brain Res. 1983 Feb;7(2):133–153. doi: 10.1016/0166-4328(83)90188-2. [DOI] [PubMed] [Google Scholar]
  53. Vizi E. S., Knoll J. The inhibitory effect of adenosine and related nucleotides on the release of acetylcholine. Neuroscience. 1976;1(5):391–398. doi: 10.1016/0306-4522(76)90132-9. [DOI] [PubMed] [Google Scholar]
  54. Vollinga R. C., de Koning J. P., Jansen F. P., Leurs R., Menge W. M., Timmerman H. A new potent and selective histamine H3 receptor agonist, 4-(1H-imidazol-4-ylmethyl)piperidine. J Med Chem. 1994 Feb 4;37(3):332–333. doi: 10.1021/jm00029a002. [DOI] [PubMed] [Google Scholar]
  55. Vorobjev V. S., Sharonova I. N., Walsh I. B., Haas H. L. Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons. Neuron. 1993 Nov;11(5):837–844. doi: 10.1016/0896-6273(93)90113-6. [DOI] [PubMed] [Google Scholar]
  56. Wada H., Inagaki N., Yamatodani A., Watanabe T. Is the histaminergic neuron system a regulatory center for whole-brain activity? Trends Neurosci. 1991 Sep;14(9):415–418. doi: 10.1016/0166-2236(91)90034-r. [DOI] [PubMed] [Google Scholar]
  57. Watanabe T., Taguchi Y., Shiosaka S., Tanaka J., Kubota H., Terano Y., Tohyama M., Wada H. Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res. 1984 Mar 12;295(1):13–25. doi: 10.1016/0006-8993(84)90811-4. [DOI] [PubMed] [Google Scholar]
  58. Westerink B. H., Damsma G., Rollema H., De Vries J. B., Horn A. S. Scope and limitations of in vivo brain dialysis: a comparison of its application to various neurotransmitter systems. Life Sci. 1987 Oct 12;41(15):1763–1776. doi: 10.1016/0024-3205(87)90695-3. [DOI] [PubMed] [Google Scholar]
  59. de Almeida M. A., Izquierdo I. Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch Int Pharmacodyn Ther. 1988 Jan-Feb;291:202–207. [PubMed] [Google Scholar]
  60. de Belleroche J., Coutinho-Netto J., Bradford H. F. Dopamine inhibition of the release of endogenous acetylcholine from corpus striatum and cerebral cortex in tissue slices and synaptosomes: a presynaptic response? J Neurochem. 1982 Jul;39(1):217–222. doi: 10.1111/j.1471-4159.1982.tb04721.x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES