Potentiation of chloride responses to glycine by three 5-HT3 antagonists in rat spinal neurones

1 Modulations of Cl- responses to glycine by 5-hydroxytryptamine ligands were studied in cultured spinal neurones, by the whole-cell recording technique. 2 Three 5-HT3 antagonists were found to potentiate reversibly responses to low concentrations of glycine. Potentiations were induced by micromolar concentrations of LY-278,584 (1-10 mu M) and by concentrations of MDL-72222 or ICS-205,930 between 10 nM and 1 mu M. 3 Potentiations were observed over the whole voltage range without any change in the reversal potential of the glycine responses and without affecting the resting conductance. 4 The degree of potentiation was variable among cells. It increased with the concentration of the modulator, but only up to 100 nM for MDL-72222 and ICS-205,930. 5 The potentiation appeared to result from an increase in the affinity for glycine of glycine receptors. 6 Neither the blockade of glycine uptake by Na+ removal, nor the excision of membrane patches prevented the potentiation. 7 At high concentrations (10 mu M), both MDL-72222 and ICS-205,930 had, in contrast, a blocking effect on glycine responses. 8 Potentiation by LY-278,584 and a dose-dependent modulation by MDL-72222 were also observed for taurine responses. 9 The effects on glycine responses of various ligands of 5-HT3 receptors (including agonists) are discussed. The ability of LY-278,584, MDL-72222 and ICS-205,930 to potentiate glycine responses appears to be independent of their known 5-HT3 receptor antagonist properties. It would be interesting to look for chemically related drugs that would be specific potentiators of glycine responses.