Selective reduction of N‐methyl‐D‐aspartate‐evoked responses by 1,3‐di(2‐tolyl)guanidine in mouse and rat cultured hippocampal pyramidal neurones

Elizabeth J. Fletcher, John Church, Khaled Abdel‐Hamid, John F. MacDonald

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13 Scopus citations

Abstract

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). In rat hippocampal neurones loaded with the Ca2+‐sensitive dye Fura‐2, DTG (10–100 μm) produced a concentration‐dependent depression of the NMDA‐evoked rises in intracellular free calcium ([Ca2+]i), an effect that was not modified by changes in the extracellular glycine concentration. DTG (at 50 and 100 μm) also attenuated, although to a lesser extent, the rises in [Ca2+]i evoked by naturally‐derived quisqualate. In contrast, 50 and 100 μm 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 [Ca2+]i. DTG attenuated NMDA‐evoked currents recorded from mouse hippocampal neurones under whole‐cell voltage‐clamp with an IC50 (mean ± s.e.mean) of 37 ± 5 μm 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. We conclude that DTG, applied at micromolar concentrations, is a selective NMDA antagonist in cultured hippocampal neurones, the block exhibiting both Mg2+‐ 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. 1993 British Pharmacological Society

Original languageEnglish
Pages (from-to)1196-1205
Number of pages10
JournalBritish Journal of Pharmacology
Volume109
Issue number4
DOIs
StatePublished - Aug 1993

Keywords

  • (RS)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA)
  • 1,3‐di(2‐tolyl)guanidine (DTG)
  • cultured hippocampal pyramidal neurones
  • Glutamate receptors
  • kainate
  • N‐methyl‐d‐aspartate (NMDA)
  • quisqualate
  • σ‐receptors

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