Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine.
The NMDA receptor agonist quinolinic acid (9 mM) was infused i.c.v. via ALZET osmotic minipumps for 2 weeks. This treatment produced a persistent, short-term memory deficit in the T-maze. Autoradiography revealed a decrease in the density of choline uptake sites in the hippocampus. Parallel s.c. infusion by another minipump of the uncompetitive NMDA receptor antagonist memantine (1-amino-3,5-dimethyladamantane, 20 mg/kg per day) or (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, 0.31 mg/kg day) prevented the learning deterioration induced by quinolinic acid. The treatment with memantine resulted in steady-state serum levels of 1.2 mu M which, based on in vitro data, should assure inhibition of NMDA receptors and are similar to levels seen in the serum of demented patients treated with this agent. In naive animals this treatment had no effect on either learning or on ex vivo induction of long-term potentiation, indicating that under chronic conditions it is possible to obtain neuroprotective effects with NMDA receptor antagonists without negative effects on memory processes. This contrasts to some acute insults (e.g. ischaemia) where high doses of NMDA receptor antagonists that produce side effects are required.
Misztal
M
M
Department of Pharmacology, Merz + Co., Eckenheimer Landstrasse, Frankfurt/M, Germany.
Frankiewicz
T
T
Parsons
C G
CG
Danysz
W
W
D000704:Analysis of Variance; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D007859:Learning Disabilities / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology*; D008570:Memory, Short-Term / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017378:Quinolinic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D017378:Quinolinic Acid; D008559:Memantine