Requirement of circadian genes for cocaine sensitization in Drosophila.
The circadian clock consists of a feedback loop in which clock genes are rhythmically expressed, giving rise to cycling levels of RNA and proteins. Four of the five circadian genes identified to date influence responsiveness to freebase cocaine in the fruit fly, Drosophila melanogaster. Sensitization to repeated cocaine exposures, a phenomenon also seen in humans and animal models and associated with enhanced drug craving, is eliminated in flies mutant for period, clock, cycle, and doubletime, but not in flies lacking the gene timeless. Flies that do not sensitize owing to lack of these genes do not show the induction of tyrosine decarboxylase normally seen after cocaine exposure. These findings indicate unexpected roles for these genes in regulating cocaine sensitization and indicate that they function as regulators of tyrosine decarboxylase.
Andretic
R
R
Department of Biology, Gilmer Hall, University of Virginia, Charlottesville, VA 22903, USA.
Chaney
S
S
Hirsh
J
J
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001522:Behavior, Animal / Q000187:drug effects; D001683:Biological Clocks / Q000235:genetics; D056926:CLOCK Proteins; D048149:Casein Kinase 1 epsilon; D002940:Circadian Rhythm / Q000235:genetics*; D003042:Cocaine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017344:Genes, Insect; D019476:Insect Proteins / Q000235:genetics / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D056950:Period Circadian Proteins; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014439:Tyramine / Q000378:metabolism / Q000494:pharmacology; D014445:Tyrosine Decarboxylase / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D048149:Casein Kinase 1 epsilon; D003042:Cocaine; D018491:Dopamine Agonists; D029721:Drosophila Proteins; D019476:Insect Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011494:Protein Kinases; D019257:Quinpirole; D017448:Receptors, Dopamine D2; D015534:Trans-Activators; D014157:Transcription Factors; D014439:Tyramine; D014445:Tyrosine Decarboxylase; C120526:Clk protein, Drosophila; C539040:PER protein, Drosophila; C112805:cyc protein, Drosophila; C113519:dco protein, Drosophila; C096445:tim protein, Drosophila