Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Alcohol-Induced Disorders, Nervous System / metabolism
-
Alcohol-Induced Disorders, Nervous System / physiopathology
-
Animals
-
Axons / drug effects
-
Axons / metabolism
-
Brain / cytology
-
Brain / drug effects
-
Brain / metabolism
-
Calcium Signaling / drug effects
-
Calcium Signaling / physiology
-
Central Nervous System Depressants / metabolism
-
Central Nervous System Depressants / pharmacology
-
Dendrites / drug effects
-
Dendrites / metabolism
-
Disease Models, Animal
-
Drosophila Proteins
-
Drosophila melanogaster / cytology
-
Drosophila melanogaster / drug effects*
-
Drosophila melanogaster / metabolism
-
Drug Resistance / drug effects
-
Drug Resistance / physiology
-
Enzyme Activation / drug effects
-
Enzyme Activation / physiology
-
Ethanol / metabolism
-
Ethanol / pharmacology*
-
Female
-
Isoenzymes / drug effects
-
Isoenzymes / genetics
-
Isoenzymes / metabolism
-
Neurons / drug effects*
-
Neurons / enzymology
-
Neurons / metabolism
-
Neuropeptide Y / drug effects*
-
Neuropeptide Y / metabolism
-
Neuropeptides / drug effects*
-
Neuropeptides / metabolism
-
Protein Kinase C / drug effects*
-
Protein Kinase C / genetics
-
Protein Kinase C / metabolism
-
RNA Interference
-
Time Factors
Substances
-
Central Nervous System Depressants
-
Drosophila Proteins
-
Isoenzymes
-
Neuropeptide Y
-
Neuropeptides
-
neuropeptide F, Drosophila
-
Ethanol
-
Protein Kinase C