Evidence that bicuculline and picrotoxin act at separate sites to antagonize γ-aminobutyric acid in rat cuneate nucleus

Bicuculline and picrotoxin have been compared over a wide range of concentrations as antagonists of γ-aminobutyric acid (GABA) and muscimol. Both antagonists caused an approximately parallel displacement of the agonist dose-response curves constructed from depolarizing responses of afferent nerve fibres in the cuneate nucleus slice. A Schild plot of log (muscimol dose ratio ? 1) vs log (bicuculline concentration) had a slope of 0.070 ± 0.032 while a similar plot for picrotoxin had a slope of 0.635 ± 0.021. When GABA was used as the agonist, the Schild plots for both antagonists had significantly lower slopes, probably due to the influence of GABA uptake processes. The degree of antagonism obtained with combinations of bicuculline and picrotoxin indicated that these two antagonists were acting at independent sites. It is concluded that bicuculline antagonizes GABA and muscimol competitively at the receptor whereas picrotoxin acts at some stage in the depolarization response mechanism.