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The Journal of Neuroscience, April 12, 2006, 26(15):3923-3932; doi:10.1523/JNEUROSCI.4883-05.2006

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Neurobiology of Disease
Low Doses of Memantine Disrupt Memory in Adult Rats

Catherine Creeley,^1,2 * David F. Wozniak,^1 * Joanne Labruyere,¹ George T. Taylor,² and John W. Olney^1 *

¹Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and ²Department of Psychology, University of Missouri, St. Louis, Missouri 63121

Correspondence should be addressed to Dr. John W. Olney, Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, St. Louis, MO 63110. Email: olneyj{at}psychiatry.wustl.edu

Memantine, a drug recently approved for treatment of Alzheimer’s disease, has been characterized as a unique NMDA antagonist that confers protection against excitotoxic neurodegeneration without the serious side effects that other NMDA antagonists are known to cause. In the present study, we determined what dose of memantine is required to protect the adult rat brain against an NMDA receptor-mediated excitotoxic process and then tested that dose and a range of lower doses to determine whether the drug in this dose range is associated with significant side effects. Consistent with previous research, we found that memantine confers a neuroprotective effect beginning at an intraperitoneal dose of 20 mg/kg, a dose that we found, contrary to previous reports, produces locomotor disturbances severe enough to preclude testing for learning and memory effects. We then determined that, at intraperitoneal doses of 10 and 5 mg/kg, memantine disrupts both memory and locomotor behaviors. Rats treated with these doses performed at control-like levels in learning a hole-board task but were significantly impaired in demonstrating what they had learned when tested 24 h later. This impairment of memory retention was not state dependent in that it was demonstrable regardless of whether the rats were or were not exposed to memantine on the day of retention testing. We conclude that, in the adult rat, memantine behaves like other NMDA antagonists in that it is neuroprotective only at doses that produce intolerable side effects, including memory impairment.

Key words: memantine; neuroprotection; memory impairment; locomotor impairment; kainic acid; NMDA antagonists

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Received Nov. 14, 2005; revised Feb. 28, 2006; accepted March 3, 2006.

Correspondence should be addressed to Dr. John W. Olney, Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, St. Louis, MO 63110. Email: olneyj{at}psychiatry.wustl.edu

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