1. Previous studies have suggested that a series of drugs modelled on part of the
strychnine molecule interfere with the development of
high pressure neurological syndrome (
HPNS) and it was presumed that this effect was via an action on inhibitory glycinergic transmission. We have now used the rat hippocampal slice preparation to examine the possibility that some of these drugs might instead have an action at the
strychnine-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 the multiple population spikes recorded in Mg(2+)-free medium. The effect of 7CK, but not AP5, was reversed by 200 microM D-
serine which is consistent with the known antagonist action of 7CK at the SI-
glycine site. 3. A derivative of
benzimidazole, which shows the clearest structural similarities to known SI-
glycine site antagonists and ameliorates
HPNS, mirrored the effects of 7CK although it was considerably less potent. 4.
Gramine, which exacerbates
HPNS, significantly increased the number of population spikes evoked in Mg(2+)-free medium. 5.
Mephenesin, which is the most potent known
drug in ameliorating
HPNS, had no significant effect on the response recorded in 1 mM Mg2+ and significantly reduced the number of population spikes recorded in Mg(2+)-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
gramine, 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 excitatory
NMDA receptor mediated transmission, rather than on inhibitory
glycine-mediated transmission.