Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions

doi:10.1016/0006-8993(81)91179-3

Brain Research

Volume 209, Issue 1, 23 March 1981, Pages 177-188

https://doi.org/10.1016/0006-8993(81)91179-3 Get rights and content

Summary

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 occured 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.

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At lower concentrations, these compounds allosterically modulate GABAA receptors to potentiate GABAergic currents. At higher concentrations, they can directly activate GABAA receptors in the absence of GABA (2, 7, 8). It has been reported that the barbiturate pentobarbital substantially potentiated peak currents and increased desensitization of α1β3δ receptor currents evoked by saturating concentrations of GABA, but that these effects of pentobarbital were not observed with α1β3γ2L receptor currents at saturating GABA concentrations, although pentobarbital enhanced α1β3γ2L currents at subsaturating GABA concentrations (8), suggesting that the δ subunit rather than the γ2L subunit confers unique “modulatory potential” for this modulator at saturating GABA concentrations.
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Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions

Summary

Brain Research

Life Sci.

Biochem. Pharmacol.

Brain Research

Brain Research

Brain Research

Exp. Neurol.

Brain Research

Acute effects of topical epileptogenic agents

Barbiturates block sodium and potassium conductance increases in voltage-clamped lobster axons

J. gen. Physiol.

Barbiturate inhibition of calcium uptake by depolarized nerve terminals in vitro

Molec. Pharmacol.

Signs and stages of anesthesia

Effect of barbiturates on release of endogenous amino acids from rat cortex slices

Neurochem. Res.

Effects of ethanol and pentobarbital on release of acetylcholine from cerebral cortex slices

J. Pharmacol. exp. Ther.

Intravenous phenytoin and phenobarbital; anticonvulsant action, brain content, and plasma binding in rat

Epilepsia (Amst.)