Drunk Worms Reveal Alcohol Tolerance Gene

Abstract

Davies et al. took advantage of allelic variation in strains of the nematode Caenorhabditis elegans to identify a gene that contributes to tolerance to the effects of ethanol exposure. C. elegans exhibits a decline in locomotor activity as an acute response to ethanol. Over time, in the continued presence of ethanol, different strains of worms, N2 and CB4856, show slow and rapid development of tolerance, respectively. Through genetic analysis, the differences in the rate of tolerance development were mapped to the nrp-1 gene, which encodes the homolog to mammalian neuropeptide Y (NPY) receptors. The CB4856 allele of npr-1 is a lower function allele than that of the N2 worms, and these different alleles of npr-1 are known to account for the worm's differences in social behaviors (N2 are solitary, CB4856 are more social and exhibit clumping behaviors). The social behavior roles of NPR-1 and the ethanol tolerance effect were separable based on genetic interactions and targeted expression studies. Worms carrying mutations in genes involved in controlling social behaviors showed no difference in ethanol tolerance rates. However, ethanol may inhibit NPR-1 signaling, because withdrawal of ethanol causes N2 worms to exhibit clumping and other social behaviors. NPY signaling is implicated in alcohol responsiveness in mammals, and further investigation with the genetically tractable nematode may lead to additional insight into the molecular mechanisms that contribute to alcoholism. A. G. Davies, J. C. Bettinger, T. R. Thilel, M. E. Judy, S. L. McIntire, Natural variation in the nrp-1 gene modifies ethanol responses of wild strains of C. elegans . Neuron 42 , 731-743 (2004). [Online Journal]