Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions.
The anesthetic-sedative barbiturate pentobarbital (PB) and the anticonvulsant barbiturate phenobarbital (PhB) were applied to mammalian spinal cord neurons in primary dissociated cell culture to assess their effects on: (1) postsynaptic GABA-responses; (2) paroxysmal activity produced by the convulsant bicuculline; (3) resting membrane properties; and (4) spontaneous neuronal activity. The results demonstrated that: (1) anticonvulsant actions occurred at barbiturate concentrations which augmented GABA-responses; (2) anesthetic actions occurred at barbiturate concentrations which produced direct increases in chloride conductance; (3) both anticonvulsant and anesthetic actions occurred at clinically relevant concentrations; and (4) concentrations of PhB, but not PB, which produced GABA-augmentation and direct conductance changes were widely separated. These findings support the hypotheses that augmentation of GABA-mediated inhibition and possibly reduction of glutamate (GLU)-mediated excitation form the basis at least in part for barbiturate anticonvulsant action and that addition of direct increases in chloride conductance to augmentation of GABA-mediated inhibition and reduction of GLU-mediated excitation may partially underlie anesthetic-sedative barbiturate action.
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D010424:Pentobarbital / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002712:Chlorides; D007473:Ion Channels; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital; D001640:Bicuculline; D010634:Phenobarbital