Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

1 The effect of a novel potentiator of glycine responses, ICS 205,930, was studied by whole-cell recordings from spinal neurones, and compared with that of other known potentiators, in an attempt to differentiate their sites of action. 2 The ability of ICS 205,930 (0.2 mu M) to potentiate glycine responses persisted in the presence of concentrations of Zn2+ (5-10 mu M) that were saturating for the potentiating effect of this ion. 3 Preincubation with 10 mu M Zn2+ before application of glycine plus Zn2+ had an inhibitory effect, which did not result from Zn2+ entry into the neurone, since it persisted with either 10 mill internal EGTA or 10 mu M internal Zn2+. To test whether the potentiating effects of ICS 205,930 and Zn2+ interact, both compounds were applied without preincubation. 4 The potentiating effect of ICS 205,930 was similar for responses to glycine and for responses to glycine plus Zn2+, provided the concentrations of agonist were adjusted so as to induce control responses of identical amplitudes. 5 ICS 205,930 remained able to potentiate glycine responses in the presence of ethanol (200 mM). 6 ICS 205,930 also retained its potentiating effect in the presence of the anaesthetic propofol (30-90 mu M), which strongly potentiated glycine responses but, in contrast with ICS 205,930, also markedly increased the resting conductance. 7 The anticonvulsant chlormethiazole (50-100 mu M) neither potentiated glycine responses nor prevented the effect of ICS 205,930, even though it increased the resting conductance and potentiated GABAA responses. 8 The mechanism of action of ICS 205,930 appears to be different from those by which Zn2+ propofol of ethanol potentiate glycine responses.