Article date: February 1996
By: Tadeusz Frankiewicz, Brigitte Potier, Zafar I. Bashir, Graham L. Collingridge, Chris G. Parsons, in Volume 117, Issue 4, pages 689-697
The effects of the uncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists, memantine (1‐amino‐3,5‐dimethyladamantane) and MK‐801 ((+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzocyclo‐hepten‐5,10‐imine maleate) were compared on synaptic transmission and long‐term potentiation (LTP) in hippocampal slices and on NMDA‐induced currents in cultured superior collicular neurones.
Memantine (10–100 μm) reversibly reduced, but did not abolish, NMDA receptor‐mediated secondary population spikes recorded in area CA1 of hippocampal slices bathed in Mg2+‐free artificial cerebrospinal fluid.
Memantine (100 μm) antagonized NMDA receptor‐mediated excitatory postsynaptic currents recorded in area CA1 in a strongly voltage‐dependent manner i.e. depressed to 11±4% of control at −35 mV and 95±5% of control at +40 mV (n=9), with no apparent effect on response kinetics.
The effects of MK‐801 and memantine on the induction of LTP were assessed after prolonged pre‐incubations with these antagonists. When present for 6.6±0.4 h prior to tetanic stimulation, memantine blocked the induction of LTP with an IC50 of 11.6±0.53 μm. By comparison, similar long pre‐incubations with MK‐801 (6.4±0.4 h) blocked the induction of LTP with an IC50 of 0.13±0.02 μm.
Memantine and MK‐801 reduced NMDA‐induced currents in cultured superior colliculus neurones recorded at −70 mV with IC50S of 2.2±0.2μm and 0.14±0.04 μm respectively. The effects of memantine were highly voltage‐dependent and behaved as though the affinity decreased ∍ fold per 50 mV of depolarization (apparent δ=0.71). In contrast, under the conditions used, MK‐801 appeared to be much less voltage‐dependent i.e. affinity decreased ∍ fold per 329 mV of depolarization (apparent δ=0.15).
Depolarizing steps from −70 mV to +50 mV in the continuous presence of memantine (10 μm) caused a rapid relief of blockade of NMDA‐induced currents from 83.7±1.9% to 21.8±1.8% (n=5). This relief was best fitted by a double exponential function (17.2±11.7 and 698±204 ms), the faster component of which was most pronounced.
In conclusion, whereas MK‐801 is equipotent in blocking NMDA‐induced currents (at −70 mV) and the induction of LTP, memantine is relatively less potent in blocking the induction of LTP. This is due to its rapid relief of blockade upon depolarization; a property which might explain its promising clinical profile in the treatment of chronic neurodegenerative diseases.
The effects of the uncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists, memantine (1‐amino‐3,5‐dimethyladamantane) and MK‐801 ((+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzocyclo‐hepten‐5,10‐imine maleate) were compared on synaptic transmission and long‐term potentiation (LTP) in hippocampal slices and on NMDA‐induced currents in cultured superior collicular neurones.
Memantine (10–100 μm) reversibly reduced, but did not abolish, NMDA receptor‐mediated secondary population spikes recorded in area CA1 of hippocampal slices bathed in Mg2+‐free artificial cerebrospinal fluid.
Memantine (100 μm) antagonized NMDA receptor‐mediated excitatory postsynaptic currents recorded in area CA1 in a strongly voltage‐dependent manner i.e. depressed to 11±4% of control at −35 mV and 95±5% of control at +40 mV (n=9), with no apparent effect on response kinetics.
The effects of MK‐801 and memantine on the induction of LTP were assessed after prolonged pre‐incubations with these antagonists. When present for 6.6±0.4 h prior to tetanic stimulation, memantine blocked the induction of LTP with an IC50 of 11.6±0.53 μm. By comparison, similar long pre‐incubations with MK‐801 (6.4±0.4 h) blocked the induction of LTP with an IC50 of 0.13±0.02 μm.
Memantine and MK‐801 reduced NMDA‐induced currents in cultured superior colliculus neurones recorded at −70 mV with IC50S of 2.2±0.2μm and 0.14±0.04 μm respectively. The effects of memantine were highly voltage‐dependent and behaved as though the affinity decreased ∍ fold per 50 mV of depolarization (apparent δ=0.71). In contrast, under the conditions used, MK‐801 appeared to be much less voltage‐dependent i.e. affinity decreased ∍ fold per 329 mV of depolarization (apparent δ=0.15).
Depolarizing steps from −70 mV to +50 mV in the continuous presence of memantine (10 μm) caused a rapid relief of blockade of NMDA‐induced currents from 83.7±1.9% to 21.8±1.8% (n=5). This relief was best fitted by a double exponential function (17.2±11.7 and 698±204 ms), the faster component of which was most pronounced.
In conclusion, whereas MK‐801 is equipotent in blocking NMDA‐induced currents (at −70 mV) and the induction of LTP, memantine is relatively less potent in blocking the induction of LTP. This is due to its rapid relief of blockade upon depolarization; a property which might explain its promising clinical profile in the treatment of chronic neurodegenerative diseases.
DOI: 10.1111/j.1476-5381.1996.tb15245.x
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