Genetic Effects in Drosophila on the Potency of Diverse General Anesthetics: A Distinctive Pattern of Altered Sensitivity

Mutations that influence the sensitivity of an organism to a volatile general anesthetic can be divided into two classes. In one, sensitivity to all other volatile agents is affected to a similar degree. Although this class may contain mutations of interest for understanding anesthesia, it is also likely to contain mutations that merely alter general health. In the second class, mutations confer non-uniform effects on potency (NEP), i.e., larger effects for some volatile anesthetics than for others. Members of this class are of special interest for studies of arousal and its pharmacological suppression because they not only avoid the pitfall of effects on global health, but also imply the existence of drug targets that are preferentially affected by particular agents. In this work, we provide the first systematic investigation of the relative frequency and diversity of NEP mutations in Drosophila. As a first step, we isolated and characterized a set of P element insertion mutations that confer altered sensitivity of the fruit fly to the clinical anesthetic halothane. Then we tested the members of this collection for their effect on the sensitivity of flies to five other volatile agents. Not only do we find that most of the mutations show non-uniform effects, they also share a characteristic arrangement of altered potencies (halothane >>desflurane >= enflurane similar to isoflurane similar to methoxyflurane >sevoflurane). From this result, although we do not know how direct or indirect are the effects of the mutations, we infer the existence of a biologically relevant target for anesthetic action that has a distinct preference for halothane over other agents. Intriguingly, P element insertions that co-map with several NEP loci have been shown to alter the fly's response to cocaine and ethanol, suggesting that common genetic elements are involved in the response to all three drugs.