Molecular Pharmacology, Vol 13, 548-559, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

The Action of Volatile Anesthetics and Convulsants on Synaptic Transmission: a Unified Concept

¹ Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

The effects of convulsant and anesthetic fluorinated ethers on synaptic transmission were studied at the frog neuromuscular junction by intracellular recording. The resting potential, input resistance, and spike threshold of the muscle fibers were unaffected by either methoxyflurane (MF, anesthetic) on hexafluorodiethyl ether (HFE, convulsant) in the concentration range from 1 nM to 1 mM. The effects of both drugs on synaptic transmission were biphasic, the end plate potential (EPP) amplitude being enhanced by low concentrations and reduced by high concentrations of the drugs. The increase in EPP amplitude was related to an increased quantal content (m), whereas reduction of the EPP was related to a decrease in the miniature EPP amplitude, which presumably was due to reduced postsynaptic sensitivity to acetylcholine. The difference in the actions of the two drugs was quantitative rather than qualitative, the effective concentrations of HFE being 10-10,000 times higher than those of MF for a corresponding effect. A model is proposed whereby these agents partition between the bulk lipids of the membrane and specific membrane subregions, in accordance with , the solubility parameter of the drug, and those of each of the holding phases. It is concluded that the fluorinated ethers act on specific sites in the membrane, probably belonging to the membrane proteins relevant to synaptic transmission.

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ACKNOWLEDGMENTS We are grateful to Dr. A. Goldschmid for helpful discussions and ideas, and also for providing us with some of the drugs, and to Professor S. Gitter for his interest and encouragement.