Abstract
We previously reported that some N-methyl-d-aspartate (NMDA)-receptor antagonists enhanced histamine neuron activity in rodents. Here, we have investigated the effects of memantine, an NMDA-receptor antagonist used for the treatment of Alzheimer's disease, on histaminergic neurotransmission. In vitro, memantine antagonized native NMDA receptors with a micromolar potency but had no effect at recombinant human histamine receptors. In vivo, a single administration of memantine increased histamine neuron activity, as shown by the 60% increase of tele-methylhistamine (t-MeHA) levels observed in the brain of mice. This increase occurred with an ED50 of 0.3 ± 0.1 mg/kg, similar to that found on inhibition of ex vivo [3H]dizocilpine maleate (MK-801) binding (1.8 ± 1.3 mg/kg). Two days after pretreatment of mice with memantine at 5 mg/kg twice daily for 5 days, t-MeHA levels were enhanced by 50 ± 7% (p < 0.001), indicating a long-lasting activation of histamine neurons. Quantitative polymerase chain reaction analysis was used to explore genes involved in this persistent effect. H3 receptor mRNAs were strongly increased, but the density of H3 receptor binding sites was increased solely in hypothalamus (by 141 ± 24%). Up-regulations of brain-derived neurotrophic factor and NMDA-receptor 1 subunit mRNAs were also found but were restricted to hippocampus. mRNA expression of α7-nicotinic receptors remained unchanged in any region. Considering the well established cognitive effects of histamine neurons, the increase in brain t-MeHA levels after single or repeated administration of therapeutic doses of memantine suggests that the drug exerts its beneficial effects on cognitive deficits of Alzheimer's disease, at least partly, by activating histamine neurons.
Footnotes
This study was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and the Syrian Ministry of Education (to M.M.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.174458.
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ABBREVIATIONS:
- hH1R
- human H1 receptor
- hH2R
- human H2 receptor
- hH3R
- human H3 receptor
- rH3R
- rat H3 receptor
- hH4R
- human H4 receptor
- t-MeHA
- tele-methylhistamine
- AD
- Alzheimer's disease
- NMDA
- N-methyl-d-aspartate
- NMDAR
- N-methyl-d-aspartate receptor
- MK-801
- dizocilpine maleate
- HEK
- human embryonic kidney
- JNJ 7777120
- 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole
- BZQ
- p-benzoquinone
- PCR
- polymerase chain reaction
- qPCR
- quantitative real-time PCR
- ANOVA
- analysis of variance
- CPX
- ciproxifan
- BDNF
- brain-derived neurotrophic factor
- NR1
- NMDA-receptor subunit 1
- α7R
- α7 receptor.
- Received August 29, 2010.
- Accepted November 4, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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