Mode of action of excitatory amino acid receptor antagonists on hippocampal long-lasting potentiation.
The effects of the N-methyl-D-aspartate receptor antagonists 2-amino-5-phosphonovalerate and gamma-D-glutamylglycine on the induction of long-lasting potentiation in the CAl and dentate areas of the hippocampal slice preparation have been examined. Synaptic activity was recorded extracellularly in the dendritic layer as a field excitatory postsynaptic potential, and the amount of long-lasting potentiation produced was measured from the change in slope of the rising phase of this potential. Experiments were generally performed with the gamma-aminobutyric acid antagonist picrotoxin in the solution. It is shown that 2-amino-5-phosphonovalerate prevents the induction of long-lasting potentiation following afferent tetanization of an input, without any effect on other inputs projecting to the same postsynaptic neurons. This result makes it unlikely that the preventive action of 2-amino-5-phosphonovalerate is related to any unspecific depressive action. Instead, 2-amino-5-phosphonovalerate was observed to block a postsynaptic depolarizing process appearing during the tetanus, likely related to current through synaptically activated N-methyl-D-aspartate receptor channels. It is suggested that 2-amino-5-phosphonovalerate prevents the induction of long-lasting potentiation by blockade of these currents through its antagonistic action on the N-methyl-D-aspartate receptors. Application of gamma-D-glutamylglycine similarly prevented the induction of long-lasting potentiation. No potentiation appeared following wash-out of the drug. The results exclude the possibility that the preventive action of this drug is related to a mere masking action on long-lasting potentiation induced in presynaptic terminals. It is suggested that gamma-D-glutamylglycine blocks the induction of long-lasting potentiation by its antagonistic action on the N-methyl-D-aspartate receptors, i.e. in a manner similar to that of 2-amino-5-phosphonovalerate.
Wigström
H
H
Gustafsson
B
B
Huang
Y Y
YY
D015763:2-Amino-5-phosphonovalerate; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects*; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D009473:Neuronal Plasticity / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D004151:Dipeptides; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C028929:gamma-glutamylglycine; D001224:Aspartic Acid; D015763:2-Amino-5-phosphonovalerate; D014633:Valine