Abstract
Histamine potentiates activation of native and recombinant N-methyl-d-aspartate receptors (NMDARs), but its mechanisms of action and physiological functions in the brain remain controversial. Using four different models, we have further investigated the histamine-induced potentiation of various NMDAR-mediated responses. In single cultured hippocampal neurons, histamine potentiated NMDA currents. It also potentiated the NMDA-induced increase in intracellular calcium in the absence, as well as with saturating concentrations, of exogenous d-serine, indicating both glycine-dependent and glycine-independent components of its effect. In rat hippocampal synaptosomes, histamine strongly potentiated NMDA-induced [3H]noradrenaline release. The profile of this response contained several signatures of the histamine-mediated effect at neuronal or recombinant NMDARs. It was NR2B-selective, being sensitive to micromolar concentrations of ifenprodil. It was reproduced by tele-methylhistamine, the metabolite of histamine in brain, and it was antagonized by impromidine, an antagonist/inverse agonist of histamine on NMDA currents. Up to now, histamine was generally considered to interact with the polyamine site of the NMDAR. However, spermine did not enhance NMDA-induced [3H]noradrenaline release from synaptosomes, and the potentiation of the same response by tele-methylhistamine was not antagonized by the polyamine antagonist arcaine. In hippocampal membranes, like spermine, tele-methylhistamine enhanced [3H]dl-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP39653) binding to the glutamate site. In contrast, spermine increased nonequilibrium [3H]5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) binding, and suppressed [3H]ifenprodil binding, whereas histamine and tele-methylhistamine had no effect. In conclusion, the histamine-induced potentiation of NMDARs occurs in the brain under normal conditions. Histamine does not bind to the polyamine site, but to a distinct entity, the so-called histamine site of the NMDAR.
Footnotes
This work was supported by Institut National de la Santé et de la Recherche Médicale. A.B. and R.F. received a support from the French Ministère de la Recherche, and R.F. received support from the Fondation pour la Recherche Médicale.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158543.
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ABBREVIATIONS:
- MeHA
- methylhistamine
- NMDAR
- N-methyl-d-aspartate receptor
- NMDA
- N-methyl-d-aspartate
- MK-801
- 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)
- NMDA(HA)R
- histamine site of the N-methyl-d-aspartate receptor
- CGP39653
- dl-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid
- AM
- acetoxymethyl ester
- ANOVA
- analysis of variance
- AP5
- dl-2-amino-5-phosphonopentanoic acid
- Ro 25-6981
- α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol
- PEAQX
- [[[(1S)-1-(4-bromophenyl)ethyl]amino] (1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl] phosphonic acid tetrasodium hydrate
- HA
- histamine
- PEA
- 2-pyridylethylamine
- GBR12909
- (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl)piperazine.
- Received July 8, 2009.
- Accepted December 10, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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