Premium
Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices
Author(s) -
Frankiewicz Tadeusz,
Potier Brigitte,
Bashir Zafar I.,
Collingridge Graham L.,
Parsons Chris G.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15245.x
Subject(s) - nmda receptor , long term potentiation , memantine , neurotransmission , neuroscience , hippocampal formation , glutamate receptor , chemistry , biology , receptor , biochemistry
1 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. 2 Memantine (10–100 μ m ) reversibly reduced, but did not abolish, NMDA receptor‐mediated secondary population spikes recorded in area CA1 of hippocampal slices bathed in Mg 2+ ‐free artificial cerebrospinal fluid. 3 Memantine (100 μ m ) 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. 4 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 IC 50 of 11.6±0.53 μ m . By comparison, similar long pre‐incubations with MK‐801 (6.4±0.4 h) blocked the induction of LTP with an IC 50 of 0.13±0.02 μ m . 5 Memantine and MK‐801 reduced NMDA‐induced currents in cultured superior colliculus neurones recorded at −70 mV with IC 50 S of 2.2±0.2μ m and 0.14±0.04 μ m 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). 6 Depolarizing steps from −70 mV to +50 mV in the continuous presence of memantine (10 μ m ) 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. 7 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.