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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Fletcher, E. J. Church, J. Abdel-hamid, K. Macdonald, J. F. |
| Description | Author Affiliation: Fletcher EJ ( Department of Physiology, University of Toronto, Ontario, Canada.) |
| Abstract | 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)-alpha-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 microM) 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 microM) also attenuated, although to a lesser extent, the rises in [Ca2+]i evoked by naturally-derived quisqualate. In contrast, 50 and 100 microM 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. 3. 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 microM 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 sigma binding sites it is unlikely that the antagonism observed here is mediated by sigma-receptors, but the data emphasize the potential danger of ascribing the functional consequences of DTG administration solely to sigma receptor-mediated events. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 109 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 1993-08-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Anticonvulsants Pharmacology Guanidines Hippocampus Physiology N-Methylaspartate Antagonists & Inhibitors Neurons Drug Effects Pyramidal Tracts Amino Acids Animals Binding, Competitive Calcium Metabolism Cells, Cultured Electric Stimulation Electrophysiology Evoked Potentials Fura-2 Mice Pregnancy Rats, Wistar Receptors, Sigma Spectrometry, Fluorescence Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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