Despite differences between the fly brain and the mammalian brain, Drosophila has been a valuable model system for studies on the genetics of alcohol sensitivity. When exposed to alcohol vapors, flies initially become hyperactive, but ultimately lose postural control; alcohol knockdown time provides a measure of sensitivity. Studies on flies have employed two complementary strategies: single mutant analyses and systems genetics approaches. A P-element mutagenesis screen for alcohol sensitivity revealed that a large fraction (approximately 30%) of the genome can contribute to alcohol sensitivity [86]. Indeed, most of the mutations that affect alcohol sensitivity in Drosophila have pleiotropic effects on other complex traits. The first mutants implicated the cyclic AMP signaling pathway, including: the cheapdate allele of amnesiac [49], which encodes a neuropeptide that activates the cyclic AMP signaling pathway [87]; the Ca2+/calmodulin-dependent adenylate cyclase encoded by the rutabaga gene [49]; and PkaR2, which encodes a cyclic AMP-dependent protein kinase [47]. In addition, mutants affecting axonal migration, neural cell adhesion and neurotransmission have also been implicated in alcohol sensitivity, including the gene encoding the axonal migration and cell adhesion receptor
