Premium
Selective reduction of N‐methyl‐D‐aspartate‐evoked responses by 1,3‐di(2‐tolyl)guanidine in mouse and rat cultured hippocampal pyramidal neurones
Author(s) -
Fletcher Elizabeth J.,
Church John,
AbdelHamid Khaled,
MacDonald John F.
Publication year - 1993
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.1476-5381.1993.tb13749.x
Subject(s) - kainate receptor , ampa receptor , nmda receptor , hippocampal formation , chemistry , biophysics , glutamate receptor , excitatory postsynaptic potential , patch clamp , cnqx , kainic acid , biochemistry , neuroscience , biology , receptor
1 The effects of 1,3‐di(2‐tolyl)guanidine (DTG) were examined on the responses of cultured hippocampal neurones to the excitatory amino acid analogues N‐methyl‐ d ‐aspartate (NMDA), kainate, quisqualate and (RS)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA). 2 In rat hippocampal neurones loaded with the Ca 2+ ‐sensitive dye Fura‐2, DTG (10–100 μ m ) produced a concentration‐dependent depression of the NMDA‐evoked rises in intracellular free calcium ([Ca 2+ ] i ), an effect that was not modified by changes in the extracellular glycine concentration. DTG (at 50 and 100 μ m ) also attenuated, although to a lesser extent, the rises in [Ca 2+ ] i evoked by naturally‐derived quisqualate. In contrast, 50 and 100 μ m DTG did not depress responses evoked by kainate, AMPA and synthetic, glutamate‐free (+)‐quisqualate although on occasions DTG enhanced kainate‐and AMPA‐evoked rises in [Ca 2+ ] i . 3 DTG attenuated NMDA‐evoked currents recorded from mouse hippocampal neurones under whole‐cell voltage‐clamp with an IC 50 (mean ± s.e.mean) of 37 ± 5 μ m at a holding potential of −60 mV. The DTG block of NMDA‐evoked responses was not competitive in nature and was not dependent on the extracellular glycine or spermine concentration. The block did, however, exhibit both voltage‐, and use‐, dependency. The steady‐state current evoked by naturally‐derived quisqualate was also attenuated by DTG whereas those evoked by kainate and AMPA were not. 4 We conclude that DTG, applied at micromolar concentrations, is a selective NMDA antagonist in cultured hippocampal neurones, the block exhibiting both Mg 2+ ‐ and phencyclidine‐like characteristics. Given the nanomolar affinity of DTG for σ binding sites it is unlikely that the antagonism observed here is mediated by σ‐receptors, but the data emphasize the potential danger of ascribing the functional consequences of DTG administration solely to σ receptor‐mediated events.