Trichloroethanol potentiates synaptic transmission mediated by gamma-aminobutyric acidA receptors in hippocampal neurons.
We have examined the actions of trichloroethanol (TCEt), the active metabolite of the general anesthetic chloral hydrate, on responses mediated by gamma-aminobutyric acid (GABA)A receptors in response to application of exogenous GABA and activation of endogenous GABAergic transmission, by using hippocampal neurons in cell culture and in brain slices. In the presence of TCEt, Cl- current activated by exogenous GABA was both enhanced in amplitude and prolonged, leading to a net increase in total charge passing through GABAA receptor channels. Prolongation of GABA-activated current increased in magnitude in a concentration-dependent manner from 0.2 to 10 mM TCEt. Inhibitory postsynaptic currents produced at synapses between pairs of cultured GABAergic neurons or by activation of interneurons in hippocampal slices were also prolonged by TCEt, at concentrations from 0.5 to 10 mM. Application of TCEt at concentrations of 1 mM and above produced a small amplitude current which was directed outwardly at -40 mV in neurons in which methylsulfate or gluconate was the major intracellular anion and directed inwardly in neurons filled with Cl-. Our observations indicate that TCEt potentiates GABAergic transmission; presumably by potentiating the function of GABAA receptors in a manner similar to barbiturate or steroid anesthetics. This action is likely to contribute to the general anesthetic effect of TCEt which occurs after chloral hydrate administration.
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tennessee.
D M
DM
Lovinger
S A
SA
Zimmerman
M
M
Levitin
M V
MV
Jones
N L
NL
Harrison
D000200:Action Potentials / Q000187:drug effects; D000768:Anesthesia, General; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels; D004357:Drug Synergism; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000777:Anesthetics; D018118:Chloride Channels; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol