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Activity of CNS depressants related to hydrophobicity

Nature volume 252, pages 52–54 (1974)Cite this article

Abstract

SEVERAL theories of general anaesthesia account for the depression of neuronal excitability as a depression of membrane mechanisms underlying axonal conduction1–4 or synaptic transmission5–16. The latter is more likely since general anaesthetics depress transmission in concentrations which do not block axonal conduction6,7,11,15,18. In vertebrates, excitatory postsynaptic potentials (epsps) are invariably depressed12,15–20, while under the same conditions inhibitory postsynaptic potentials (ipsps)4,21–23 and excitatory presynaptic potentials (resulting in presynaptic inhibition) are preserved (and prolonged)24–27. Using invertebrate preparations we found28 that (1) pentobarbital selectively and reversibly depresses Na+-dependent epsps without affecting either Cl−- or K+-dependent ipsps, and (2) pentobarbital and other central nervous system (CNS) depressants selectively and reversibly depress postsynaptic excitation (induced by application of putative transmitters) which is coupled primarily to an increase in Na+ conductance without affecting postsynaptic inhibition (induced by application of putative transmitters) which is coupled to either Cl− or K+ conductance increases. Selective depression of postsynaptic excitation would presumably lead to a decrease in the ratio of epsps to ipsps and thus account for much of the generalised decrease in neuronal activity during general anaesthesia. The observations by Meyer29 and Overton30 that general anaesthetic potency is directly proportional to the oil/water partition coefficient have prompted me to investigate the correlation between depressant activity and hydrophobicity. I report here that (1) depressant activity on invertebrate postsynaptic membranes is quantitatively correlated with hydrophobicity (r=0.982), and (2) analysis of published data from a vertebrate preparation indicates that the ratio of drug concentrations depressing axonal conduction and synaptic transmission equally is also quantitatively correlated with hydrophobicity (r = 0.96).

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  1. Behavioral Biology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20014

    JEFFERY L. BARKER

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BARKER, J. Activity of CNS depressants related to hydrophobicity. Nature 252, 52–54 (1974). https://doi.org/10.1038/252052a0

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