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Titolo:
EFFECTS OF MEMANTINE AND MK-801 ON NMDA-INDUCED CURRENTS IN CULTURED NEURONS AND ON SYNAPTIC TRANSMISSION AND LTP IN AREA CA1 OF RAT HIPPOCAMPAL SLICES
Autore:
FRANKIEWICZ T; POTIER B; BASHIR ZI; COLLINGRIDGE GL; PARSONS CG;
Indirizzi:
MERZ & CO,DEPT PHARMACOL,ECKENHEIMER LANDSTR 100-104 D-60318 FRANKFURT 1 GERMANY MERZ & CO,DEPT PHARMACOL D-60318 FRANKFURT 1 GERMANY UNIV BIRMINGHAM,SCH MED,DEPT PHARMACOL BIRMINGHAM B15 2TT W MIDLANDS ENGLAND
Titolo Testata:
British Journal of Pharmacology
fascicolo: 4, volume: 117, anno: 1996,
pagine: 689 - 697
SICI:
0007-1188(1996)117:4<689:EOMAMO>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
LONG-TERM POTENTIATION; GAMMA-AMINOBUTYRIC-ACID; INTRACEREBRAL MICRODIALYSIS; ANTICONVULSANT MK-801; RECEPTOR CHANNELS; AMINO-ACIDS; ASPARTATE; GLUTAMATE; ISCHEMIA; ANTAGONIST;
Keywords:
MEMANTINE (1-AMINO-3,5-DIMETHYLADMANTANE); MK-801 (DIZOCILPINE); LTP (LONG-TERM POTENTIATION); NMDA (N-METHYL-D-ASPARTATE); HIPPOCAMPAL SLICE; AREA CAI; PATCH CLAMP; KINETICS; VOLTAGE-DEPENDENCY; SUPERIOR COLLICULUS CULTURE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
60
Recensione:
Indirizzi per estratti:
Citazione:
T. Frankiewicz et al., "EFFECTS OF MEMANTINE AND MK-801 ON NMDA-INDUCED CURRENTS IN CULTURED NEURONS AND ON SYNAPTIC TRANSMISSION AND LTP IN AREA CA1 OF RAT HIPPOCAMPAL SLICES", British Journal of Pharmacology, 117(4), 1996, pp. 689-697

Abstract

1 The effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, memantine (1-amino-3,5-dimethyladamantane) and MK-801 yl-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 mu M) 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 mu 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 preincubations 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 mu M. By comparison, similar long preincubations with MK-801 (6.4+/-0.4h) blocked the induction of LTP with an IC50 of 0.13+/-0.02 mu M. 5 Memantine and MK-801 reduced NMDA-induced currents in cultured superiorcolliculus neurones recorded at -70 mV with IC(50)s of 2.2+/-0.2 mu Mand 0.14+/-0.04 mu M respectively. The effects of memantine were highly voltage-dependent and behaved as though the affinity decreased epsilon fold per 50 mV of depolarization (apparent delta=0.71). In contrast, under the conditions used, MK-801 appeared to be much less voltage-dependent i.e. affinity decreased epsilon fold per 329 mV of depolarization (apparent delta=0.15). 6 Depolarizing steps from -70 mV to +50 mV in the continuous presence of memantine (10 mu 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 propertywhich might explain its promising clinical profile in the treatment of chronic neurodegenerative diseases.

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Documento generato il 15/07/20 alle ore 14:59:27