Electrophysiological Evidence for Increased Calcium-Mediated Potassium Conductance by Low-Dose Sedative-Hypnotic Drugs

Abstract

In this chapter evidence is presented favoring the hypothesis that low-dose actions (i. e., mild sedation and anxiolysis) of ethanol, a water-soluble benzodiazepine (midazolam), and pentobarbital are due to enhanced calcium-mediated potassium conductance (Ca-gK). This hypothesis, which developed from results of electrophysiological experiments recording intracellularly from CA1 and CA3 cells in mammalian hippocampal slices, centers around the fact that injection of Ca²⁺ into excitable cells induces a membrane hyperpolarization by a selective increase in gK [20,24,30,32,33]. Physiologically, Ca-gK is usually triggered by a depolarization-induced influx of Ca²⁺ from the surrounding medium. On the other hand, persistently raised intracellular free Ca²⁺ concentration, [Ca²⁺]_i, will actually reduce the depolarization-induced inward Ca²⁺ current [14,16,20,24,37,43]. However, it was shown in voltage-clamped dorid neurons that the intraneuronal free [Ca²⁺]_i and not the amount of the Ca²⁺ current is related to the degree of activation of the Ca-gK [15]. Therefore, Ca-gK could be increased even though the inward Ca²⁺ current is reduced if the source of increased [Ca²⁺]_i is intracellular. The exact way that Ca-gK is activated by a depolarizing current pulse or by injected Ca²⁺ is unclear. We have used the size of the Ca²⁺ spikes evoked in neurons perfused with tetrodotoxin (TTX), which blocks Na⁺-dependent action potentials, as an indirect monitor of the free [Ca²⁺]_i.