Chronic treatment with the uncompetitive NMDA receptor antagonist memantine influences the polyamine and glycine binding sites of the NMDA receptor complex in aged rats.
Receptor binding studies on rat cortical membranes were used to characterize the NMDA receptor in aged rats (22 months) treated for 20 months with a memantine containing diet delivering 30 mg/kg/day in comparison to aged and young/adult rats treated with control-diet. Spatial memory impairing effects of (+)-MK-801 (0.16 mg/kg) in the radial maze was not altered within the course of memantine-treatment (up to 16 months). However, chronic memantine-treatment significantly increased the number of [3H]MK-801 binding sites and the affinity of [3H]glycine. A non-significant trend to such changes was also seen in aged-control rats. Glycine-dependent [3H]MK-801 binding (functional binding under non-equilibrium conditions at a fixed L-glutamate concentration) revealed that a decreased ability of glycine to stimulate channel opening in aged rats was partially attenuated by the long-term memantine treatment. Furthermore, an increased ability of spermidine to enhance [3H]MK-801 binding in aged-control rats was even more pronounced in the aged memantine-treated group. Together these findings may indicate that changes in functional receptor-channel properties during the process of aging occur prior to a detectable loss of binding sites and that memantine enhances an endogenous compensatory mechanism triggered by glutamatergic hypofunction which is suggested to take place in aging.
Bresink
I
I
Department of Pharmacology, Merz + Co. GmbH & Co., Frankfurt/Main, Federal Republic of Germany.
Danysz
W
W
Parsons
C G
CG
Tiedtke
P
P
Mutschler
E
E
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013095:Spermidine / Q000494:pharmacology
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D005998:Glycine; D013095:Spermidine; D008559:Memantine