Abstract
Memantine, a low- to moderate-affinity uncompetitive N-methyl-d-aspartate receptor antagonist, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). In the present study, the effect of memantine on locomotor activity, social behavior, and spatial learning was assessed in a transgenic mouse model of AD. Eight-month-old male C57BL/6J mice carrying mutated human APP and PS1 genes (APP/PS1) and their nontransgenic (NT) litter mates were administered a therapeutic dose of memantine (30 mg/kg/day p.o.) for 2 to 3 weeks. At this age, APP/PS1 mice show elevated levels of β-amyloid peptides in several brain regions. APP/PS1 mice exhibited less exploratory rearing and increased aggressive behavior compared with NT mice. In the water maze test for spatial learning, APP/PS1 mice had longer escape latencies to both hidden and visible platforms, but they did not differ from NT mice in their swimming speed. Memantine significantly improved the acquisition of the water maze in APP/PS1 mice without affecting swimming speed. Memantine did not affect either locomotor activity or aggressive behavior in either genotype. These data indicate that memantine improves hippocampus-based spatial learning in a transgenic mouse model of AD without producing nonspecific effects on locomotion/exploratory activity.
Footnotes
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This study was supported by the Academy of Finland and Forest Laboratories, Inc. (Jersey City, NJ). This work was previously presented at the following scientific meetings: Tanila H, Minkeviciene R, and Banerjee P (2003) The 34th annual meeting of the American Society for Neurochemistry; May 3-7, 2003; Newport Beach, CA: behavioral effects of subchronic memantine treatment in APP/PS1 double mutant mice modeling Alzheimer's disease (Abstract). J Neurochem. 85 (Suppl 1):42. Tanila H, Minkeviciene R, and Banerjee P (2003) The 11th Congress of the International Psychogeriatric Association; August 17-22, 2003; Chicago, IL: behavioral effects of subchronic memantine treatment in APP/PS1 double mutant mice modeling Alzheimer's disease (Abstract). Int Psychogeriatr. 15 (Suppl 2):326. Tanila H, Minkeviciene R, and Banerjee P (2003) The 16th Congress of the European College of Neuropsychopharmacology; September 20-24, 2003; Prague, Czech Republic: behavioral effects of subchronic memantine treatment in APP/PS1 double mutant mice modeling Alzheimer's disease (Abstract). Eur Neuropsychopharmacol. 13 (Suppl 4):S392.
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doi:10.1124/jpet.104.071027.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; AD, Alzheimer's disease; MK-801, dizocilpine maleate; Aβ, beta amyloid; PS, presenilin; APP, amyloid precursor protein; LTP, long-term potentiation; APPswe, amyloid precursor protein with Swedish mutation; NT, nontransgenic; ANOVA, analysis of variance; 5-HT, 5-hydroxytryptamine (serotonin).
- Received May 5, 2004.
- Accepted June 9, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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Memantine Improves Spatial Learning in a Transgenic Mouse Model of Alzheimer's Disease
