Summary
It is often assumed that sedative drugs cause neuronal depression by activating GABAergic mechanisms. Using intracellular recordings from in-vitro rat and guinea pig CA1 and CA3 neurons, this lab is studying the ionic mechanisms of lower, non-anesthetic doses of ethanol (≤20mM), pentobarbital (< 100 uM) and 2 benzodiazepines (midazolam and clonazepam (≤10−8M). All drugs caused a hyperpolarization, usually with moderately increased conductance and decreased spontaneous spiking. Intracellular chloride injection had no effect on these responses. Post-spike long-lasting afterhyperpolarizatons (AHPs), thought to be due to Ca++ -mediated K+ conductance (Ca-gK), were consistently enhanced by these drugs. In the presence of TTX, Ca++ spikes were examined. Ethanol and pentobarbital had no effect or tended to diminish whereas midazolam enhanced these Ca++ spikes. Zero Ca++ perfusate did not prevent ethanol or pentobarbital actions, but blocked midazolam actions. Intracellularly injected cesium, which blocks gK, blocked ethanol effects. Low drug doses had no effect or slightly diminished GABA actions, whereas higher (anesthetic) doses tended to enhance GABA actions.
We conclude that: 1) All these sedative drugs cause neuronal inhibtion at non-anesthetic doses by augmenting Ca-gK and not GABA actions or gCl. 2) Ethanol and pentobarbital, which tend to diminish Ca++ spikes, augment Ca-gK possibly by increasing intracellular [Ca++] from intracellular stores. 3) Hawever, benzodiazepine neuronal inhibiton can be explained by increasing inward Ca++ flux which then activates gK.
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© 1986 Martinus Nijhoff Publishing, Boston
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Carlen, P.L., Gurevich, N., Davies, M.F., Blaxter, T.J., O’Beirne, M. (1986). Calcium Currents and Potassium Conductance Changes Explain Low-Dose Sedative Drug Actions in Mammalian Hippocampal Neurons. In: Rahamimoff, R., Katz, B. (eds) Calcium, Neuronal Function and Transmitter Release. Topics in the Neurosciences, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2307-5_32
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DOI: https://doi.org/10.1007/978-1-4613-2307-5_32
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