POSSIBLE NMDA ANTAGONIST PROPERTIES OF DRUGS THAT AFFECT HIGH-PRESSURE NEUROLOGICAL SYNDROME

1 Previous studies have suggested that a series of drugs modelled on p art of the strychnine molecule interfere with the development of high pressure neurological syndrome (HPNS) and it was presumed that this ef fect was via an action on inhibitory glycinergic transmission. We have now used the rat hippocampal slice preparation to examine the possibi lity that some of these drugs might instead have an action at the stry chnine-insensitive (SI) glycine binding site associated with the NMDA receptor. 2 D-2-Amino-5-phosphonovalerate (AP5) and 7-chlorokynurenate (7CK) had no significant effect on the height of the population spike recorded from the CA1 region in 1 mM Mg2+ medium, but both blocked th e multiple population spikes recorded in Mg2+-free medium. The effect of 7CK, but not AP5, was reversed by 200 mu M D-serine which is consis tent with the known antagonist action of 7CK at the SI-glycine site. 3 A derivative of benzimidazole, which shows the dearest structural sim ilarities to known SI-glycine site antagonists and ameliorates HPNS, m irrored the effects of 7CK although it was considerably less potent. 4 Gramine, which exacerbates HPNS, significantly increased the number o f population spikes evoked in Mg2+-free medium. 5 Mephenesin, which is the most potent known drug in ameliorating HPNS, had no significant e ffect on the response recorded in 1 mM Mg2+ and significantly reduced the number of population spikes recorded in Mg2+-free medium, but this effect was only partially reversed by the addition of D-serine. 6 The results are consistent with the benzimidazole derivative, but not gra mine, being an antagonist at the SI-glycine receptor. The results with mephenesin are equivocal but leave open the possibility that some of the drugs which are effective against HPNS act via an effect on excita tory NMDA receptor-mediated transmission, rather than on inhibitory gl ycine-mediated transmission.