title: Zebrafish reward mutants reveal novel transcripts mediating the behavioral effects of amphetamine.
abstract: BACKGROUND
  Addiction is a pathological dysregulation of the brain's reward systems, determined by several complex genetic pathways. The conditioned place preference test provides an evaluation of the effects of drugs in animal models, allowing the investigation of substances at a biologically relevant level with respect to reward. Our lab has previously reported the development of a reliable conditioned place preference paradigm for zebrafish. Here, this test was used to isolate a dominant N-ethyl-N-nitrosourea (ENU)-induced mutant, no addiction (nad(dne3256)), which fails to respond to amphetamine, and which we used as an entry point towards identifying the behaviorally relevant transcriptional response to amphetamine.
  
  
  RESULTS
  Through the combination of microarray experiments comparing the adult brain transcriptome of mutant and wild-type siblings under normal conditions, as well as their response to amphetamine, we identified genes that correlate with the mutants' altered conditioned place preference behavior. In addition to pathways classically involved in reward, this gene set shows a striking enrichment in transcription factor-encoding genes classically involved in brain development, which later appear to be re-used within the adult brain. We selected a subset of them for validation by quantitative PCR and in situ hybridization, revealing that specific brain areas responding to the drug through these transcription factors include domains of ongoing adult neurogenesis. Finally, network construction revealed functional connections between several of these genes.
  
  
  CONCLUSIONS
  Together, our results identify a new network of coordinated gene regulation that influences or accompanies amphetamine-triggered conditioned place preference behavior and that may underlie the susceptibility to addiction.
authors: Department Zebrafish Neurogenetics, Institute of Developmental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Ingolstaedter Landstrasse, Neuherberg, 85764 Germany. katharine.webb@helmholtz-muenchen.de
authors: Katharine J
authors: KJ
authors: Webb
authors: William Hj
authors: WH
authors: Norton
authors: Dietrich
authors: D
authors: Trümbach
authors: Annemarie H
authors: AH
authors: Meijer
authors: Jovica
authors: J
authors: Ninkovic
authors: Stefanie
authors: S
authors: Topp
authors: Daniel
authors: D
authors: Heck
authors: Carsten
authors: C
authors: Marr
authors: Wolfgang
authors: W
authors: Wurst
authors: Fabian J
authors: FJ
authors: Theis
authors: Herman P
authors: HP
authors: Spaink
authors: Laure
authors: L
authors: Bally-Cuif
mesh_terms: D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017403:In Situ Hybridization; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics* / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C492589:gfi1ab protein, zebrafish; D000661:Amphetamine