Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists

Behavioral changes have previously been reported following administrations of uncompetitive NMDA receptor antagonists memantine, amantadine and MK-801 for 14 days, at the doses that produce plasma levels comparable to those seen in patients (20, 100 and 0.31mg/kg/day respectively). Using the same doses, the effect on receptor binding (autoradiography) was studied in rats. [H-3]MK-801 binding was increased in the dentate gyrus and CA3 region of the hippocampus (35.2 and 24.3% respectively) following 3 days S.C. infusion of memantine by ALZET minipumps. One daily injection of memantine for 14 days, increased [H-3]MK-801 binding in the frontal cortex by 40.3%. The same treatment with amantadine did increase [H-3]raclopride binding to dopamine D-2 receptors by 13.5%. None of these treatments changed the expression of muscarinic receptors. It is concluded that subchronic blockade of the NMDA receptor by uncompetitive antagonists at moderate (therapeutically-relevant) doses induced only minor changes in NMDA and dopamine D-2 receptor expression.