title: Functional dissection of neuroanatomical loci regulating ethanol sensitivity in Drosophila.
abstract: Ethanol has complex but similar effects on behavior in mammals and the fruit fly Drosophila melanogaster. In addition, genetic and pharmacological approaches have implicated the cAMP pathway in the regulation of ethanol-induced behaviors in both flies and rodents. Here we examine the neuroanatomical loci that modulate ethanol sensitivity in Drosophila by targeting the expression of an inhibitor of cAMP-dependent protein kinase (PKA) to specific regions in the fly's brain. Expression of the inhibitor in most brain regions or in muscle has no effect on behavior. In contrast, inhibition of PKA in a relatively small number of cells, possibly neurosecretory cells, in the fly's brain is sufficient to decrease sensitivity to the incoordinating effects of ethanol. Additional brain areas are, however, also involved. The mushroom bodies, brain structures where cAMP signaling is required for olfactory classical conditioning, are dispensable for the regulation of ethanol sensitivity. Finally, different behavioral effects of ethanol, motor incoordination and sedation, appear to be regulated by PKA function in distinct brain regions. We conclude that the regulation of ethanol-induced behaviors by PKA involves complex interactions among groups of cells that mediate either increased or reduced sensitivity to the acute intoxicating effects of ethanol.
authors.affiliation: Department of Anatomy, University of California, San Francisco, California 94143-0452, USA.
authors.forename: Aylin R
authors.initials: AR
authors.lastname: Rodan
authors.forename: John A
authors.initials: JA
authors.lastname: Kiger
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heberlein
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000187:drug effects; D020134:Catalytic Domain / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000502:physiology*; D004351:Drug Resistance / Q000235:genetics; D000431:Ethanol / Q000493:pharmacokinetics / Q000494:pharmacology*; D015870:Gene Expression; D017930:Genes, Reporter; D006918:Hydroxyurea / Q000494:pharmacology; D007814:Larva; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D024521:Mushroom Bodies / Q000187:drug effects / Q000502:physiology; D009420:Nervous System / Q000033:anatomy & histology / Q000187:drug effects*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes
chemical_list: D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000431:Ethanol; D017868:Cyclic AMP-Dependent Protein Kinases; D006918:Hydroxyurea