To help define the physiological targets of general anesthetics, we are isolating mutations of Drosophila melanogaster that alter the effectiveness of these agents. In the past both new and existing mutants have been characterized by a simple behavioral assay of the fly's capacity to retain an upright posture and by a more sophisticated electrophysiological analysis of an escape reflex. To supplement our repertory of behavioral assays we have now developed a """"""""distribution"""""""" test that measures the fly's capacity to climb up the side of a tube after being shaken to its bottom. This test provides a rapid and sensitive assay that can be performed reliably with a smaller number of individuals than our other assays. Mutants isolated as resistant to the effects of halothane by the postural test are hypersensitive to halothane in the distribution test, confirming that these mutations do not eliminate the principal target of halothane in the organism. To refine our electrophysiological analysis, we have redesigned the setup to reduce the flow of anesthetic by a factor of approximately 1,000. This will permit studies with research anesthetics that are available only in limited quantity. We have also used this setup to test the effect of halothane on different wild-type strains of Drosophila. Surprisingly, we find that substantial differences in sensitivity exist between these lines. We conclude that studies of mutants will have to be exquisitely controlled for genetic background. Finally, we have tested the escape response by behavioral, as opposed to electrophysiological, methods in free-ranging flies. The sensitivity to halothane in both assays is comparable, confirming the value of the escape response as a tool for identifying physiological targets of this agent.

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Burg, E D; Langan, S T; Nash, H A (2013) Drosophila social clustering is disrupted by anesthetics and in narrow abdomen ion channel mutants. Genes Brain Behav 12:338-47
Peabody, Nathan C; Pohl, Jascha B; Diao, Fengqiu et al. (2009) Characterization of the decision network for wing expansion in Drosophila using targeted expression of the TRPM8 channel. J Neurosci 29:3343-53
Sandstrom, David J (2008) Isoflurane reduces excitability of Drosophila larval motoneurons by activating a hyperpolarizing leak conductance. Anesthesiology 108:434-46
Cheng, Yuzhong; Nash, Howard A (2008) Visual mutations reveal opposing effects of illumination on arousal in Drosophila. Genetics 178:2413-6
Cheng, Yuzhong; Nash, Howard A (2007) Drosophila TRP channels require a protein with a distinctive motif encoded by the inaF locus. Proc Natl Acad Sci U S A 104:17730-4
Humphrey, John A; Hamming, Kevin S; Thacker, Colin M et al. (2007) A putative cation channel and its novel regulator: cross-species conservation of effects on general anesthesia. Curr Biol 17:624-9
Yu, James X; Guan, Zhonghui; Nash, Howard A (2006) The mushroom body defect gene product is an essential component of the meiosis II spindle apparatus in Drosophila oocytes. Genetics 173:243-53
Rajaram, Shantadurga; Scott, Robert L; Nash, Howard A (2005) Retrograde signaling from the brain to the retina modulates the termination of the light response in Drosophila. Proc Natl Acad Sci U S A 102:17840-5
Sandstrom, David J; Nash, Howard (2004) Drug targets: turning the channel (on) for sedation. Curr Biol 14:R185-6
Sandstrom, David J (2004) Isoflurane depresses glutamate release by reducing neuronal excitability at the Drosophila neuromuscular junction. J Physiol 558:489-502

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