Enhanced neuronal K+ conductance: a possible common mechanism for sedative-hypnotic drug action

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Abstract
It is commonly thought that CNS depressant drugs exert their actions through enhancement of GABA mediated mechanisms. The cellular electrophysiological evidence from this laboratory and others suggests that sedative hypnotics and general anesthetics inhibit central neurons by increasing K conductance (GK). Mammalian in vitro hippocampal and cerebellar slice preparations were used at 34-36.degree. C. Intracellular recordings from CA1, CA3 and cerebellar Purkinje cells were obtained. Low dose (sedative) concentrations of ethanol (.ltoreq. 20 mM), 2 different bezodiazepines (midazolam and clonazepam in low nM concentrations) and pentobarbital (10-6 to 10-4 M) were applied by pressure ejection or were bath perfused. All drugs caused a hyperpolarization with decreased spontaneous activity and enhanced post spike afterhyperpolarizations (AHP). These long-lasting AHP are presumably due to enhanced Ca mediated GK. Increased responsiveness to focally applied GABA was only seen at higher doses (ethanol, 100 mM; midazolam, 10-7 M; pentobarbital, 10-4 M). The above neurodepressant drugs, when applied at sedative doses to hippocampal pyramidal cells evidently enhance GK and not the actions of GABA.