Multiple actions of convulsant barbiturates on mouse neurons in cell culture.
The convulsant barbiturate 5-(2-cyclohexylidene-ethyl)-5-ethyl barbituric acid (CHEB) depolarized most (greater than 90%) mouse spinal cord (SC) neurons in primary dissociated cell culture in a concentration-dependent fashion with threshold effects at 10 to 50 nM. Dorsal root ganglion (DRG) neurons were also depolarized by CHEB, but only about 50% of the neurons responded. The threshold concentration for depolarization of DRG neurons was several hundred-fold higher than for SC neurons. CHEB depolarizations may be mediated by an increase in a cation conductance which is calcium-dependent because CHEB depolarizations had an extrapolated reversal potential near 0 mV, were insensitive to intracellular anion (chloride ion) injection, were absent after removal of extracellular calcium ions and were reduced by cadmium ions. In contrast, the nonconvulsant barbiturates, pentobarbital and phenobarbital, did not produce membrane depolarization. However, at concentrations of CHEB somewhat higher than those which directly depolarized cells, CHEB resembled pentobarbital and phenobarbital because it reduced the spontaneous activity of SC neurons and shortened calcium-dependent action potentials of DRG neurons. Two other convulsant barbiturates, trans-5-ethyl-5-(3'-methyl-but-2'-enyl) barbituric acid and trans-5-ethyl-5-(1',3'-dimethyl-but-1'-enyl) barbituric acid, also produced membrane depolarization, reduced spontaneous activity and shortened calcium-dependent action potentials. Another convulsant barbiturate, S(+)-1-methyl-5-phenyl-5-propyl barbituric acid, did not alter membrane potential or conductance of SC neurons, suggesting that mechanistic subclasses of convulsant barbiturates exist.(ABSTRACT TRUNCATED AT 250 WORDS)
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003292:Convulsants / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D013779:Tetrodotoxin / Q000494:pharmacology
D001463:Barbiturates; D002104:Cadmium; D002118:Calcium; D003292:Convulsants; D010424:Pentobarbital; D010852:Picrotoxin; D013779:Tetrodotoxin; C020322:5-ethyl-5-(3'-methylbut-2'-enyl)barbituric acid; C042236:5-ethyl-5-(1,3-dimethyl-1-butenyl)barbituric acid