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

• Published in: British journal of pharmacology 1996-02, Vol.117 (4), p.689-697
• Main Authors: Frankiewicz, Tadeusz, Potier, Brigitte, Bashir, Zafar I., Collingridge, Graham L., Parsons, Chris G.
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; area CA1; Biological and medical sciences; Cells, Cultured; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; hippocampal slice; Hippocampus - drug effects; Hippocampus - physiology; In Vitro Techniques; kinetics; Long-Term Potentiation - drug effects; LTP (long‐term potentiation); Male; Medical sciences; Memantine (1‐amino‐3,5‐dimethyladmantane); Memantine - pharmacology; MK‐801 (dizocilpine); N-Methylaspartate - antagonists & inhibitors; N-Methylaspartate - pharmacology; Neurons - cytology; Neurons - drug effects; Neuropharmacology; Neuroprotective agent; NMDA (N‐methyl‐D‐aspartate); patch clamp; Pharmacology. Drug treatments; Rats; superior colliculus culture; Synaptic Transmission - drug effects; voltage‐dependency
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15245.x

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 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. 3 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. 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 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. 5 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). 6 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. 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.