Activity-dependent regulation of ion channel gene expression: a homeostatic hypothesis for drug tolerance

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Ghezzi, Alfredo

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Conservation of the balance between excitation and inhibition of neural activity is critically important for the proper function of the nervous system. Upon alterations in excitability, the nervous system may thus trigger mechanisms that attempt to restore homeostasis. Many alcohols, anesthetics, and other abused volatile solvents such as ethanol, benzyl alcohol, toluene, trichloroethylene, and chloroform alter neural excitability and trigger homeostatic adaptations that through the modulation of gene expression and signaling between nerve cells act to counteract these alterations. Many of these adaptations may account for the development of tolerance, dependence and addiction to these drugs. Here, I demonstrate that in Drosophila, tolerance to the sedative effects of alcohols and anesthetics, is mediated by an increase in expression of the Ca2+ activated K+ channel gene, slowpoke. A mutation that eliminates slowpoke expression prevents tolerance, while expression from an inducible slowpoke transgene mimics tolerance in naive animals. Furthermore, the behavioral and molecular response to volatile solvents can be separated into an initial phase of hyperkinesis that causes a drop in slowpoke gene expression and makes animals more sensitive to subsequent sedation by these drugs, and a sedative phase that stimulates slowpoke gene expression and induces tolerance. This demonstrates that the changes in expression level of slowpoke act as a modulator of drug sensitivity. Because of it's central role as a regulator of electrical activity in nerve terminals this channel gene is a likely contributor to the homeostatic mechanism that resists untoward changes in net cellular excitability and mediates tolerance to sedation. If hyperexcitability is induced, the proposed mechanism alters channel expression to reduce this excitability, whereas if cellular excitability is suppressed, channel gene expression changes to enhance excitability. An electrophysiological test of this hypothesis shows that increased slowpoke expression enhances the excitability of a neural pathway in a way that opposes the effects of sedative drugs. This data supports the notion that slowpoke mediated tolerance to sedation is part of a homeostatic adaptation that compensates for changes in neural activity caused by drugs and represents a step forward in the understanding of the molecular basis of drug addiction.