COMPARATIVE PATCH-CLAMP STUDIES WITH FRESHLY DISSOCIATED RAT HIPPOCAMPAL AND STRIATAL NEURONS ON THE NMDA RECEPTOR ANTAGONISTIC EFFECTS OF AMANTADINE AND MEMANTINE

Patch- and concentration-clamp techniques were used to compare the eff ects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagon ists (+)-MK-801 (dizocilpine, (+)-5-methyl-10,11-dihydro-5H-dibenzo cy clohepten-5,10-imine maleate), ketamine, memantine (1-amino-3,5-dimeth yladamantane) and amantadine (1-amino-adamantane) on agonist-induced i nward currents in freshly dissociated rat hippocampal and striatal neu rons. In hippocampal neurons, ketamine (5 mu M), memantine (10 mu M) a nd amantadine (100 mu M) selectively antagonized inward current respon ses to NMDA (500 gamma M plus glycine 5 mu M) in a voltage-dependent m anner without affecting responses to lpha-amino-3-hydroxy-5-methyl-4-i soxazolepropionic acid (100 mu M) or gamma-aminobutyric acid (10 mu M) . The NMDA receptor antagonistic effect of all four agents was typical of open channel blockade. The kinetics of blockade/unblockade was inv ersely related to antagonist affinity. In hippocampal neurons amantadi ne was the least potent NMDA receptor antagonist (IC50 18.6 +/- 0.9 mu M) and showed the fastest blocking kinetics, whereas (+)-MK-801 was t he most potent (IC50 0.12 +/- 0.01 mu M) and showed the slowest blocki ng kinetics. Memantine (IC50 1.04 +/- 0.26 mu M) and ketamine (IC50 0. 43 +/- 0.10 mu M) were almost equipotent and had similar, intermediate blocking kinetics. In striatal neurons recorded under identical condi tions (+)-MK-801, ketamine and memantine were 3- to 4-fold less potent whereas amantadine was somewhat more potent than on hippocampal neuro ns. This could offer an explanation for the better clinical profile of amantadine in Parkinson's disease, as therapeutically relevant concen trations of amantadine are likely to be more active in the striatum wh ereas memantine is likely to be more active in other structures.