A protein kinase C activity localized to neuropeptide Y-like neurons mediates ethanol intoxication in Drosophila melanogaster

Neuropeptide Y (NPY) regulates acute ethanol sensitivity and voluntary alcohol consumption in rodents. In Drosophila melanogaster, NPY-like neuropeptide F (NPF) and its receptor NPFR1 display a parallel function, suggesting that an evolutionarily conserved mechanism may underlie similar behavioral effects of ethanol in diverse organisms. We have used the fly model to uncover novel genes and molecular pathways important for acute ethanol response. Here we report a critical role of the conserved protein kinase C (PKC) pathway in mediating the intoxicating effect of ethanol. Flies expressing a pseudo-substrate inhibitor of PKC, directed by npf-gal4, displayed decreased ethanol sensitivity. Furthermore, the RNA interference analysis suggests that a calcium-independent PKC isoform (PKC98E, related to mammalian novel PKCs) is largely responsible for the behavioral phenotype. Finally, we provide evidence that the NPF/PKC-dependent mechanism selectively affects acute sensitivity but not rapid tolerance to ethanol intoxication. These findings reveal an uncharacterized role of PKC in NPY/NPF-mediated acute ethanol sensitivity in flies and possibly mammals. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.