title: Hippocampal CA1 region shows differential regulation of gene expression in mice displaying extremes in behavioral sensitization to amphetamine: relevance for psychosis susceptibility?
abstract: BACKGROUND
  Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis.
  
  
  OBJECTIVE
  The aim of the current study was to investigate which genes and pathways may contribute to behavioral sensitization in different dopaminergic output areas in the mouse brain.
  
  
  METHODS
  We took advantage of the naturally occurring difference in psychostimulant sensitivity in DBA/2 mice and selected animals displaying extremes in behavioral sensitization to amphetamine. Subsequently, the dopamine output areas, prefrontal cortex, nucleus accumbens, and cornu ammonis 1 (CA1) area of the hippocampus, were isolated by laser microdissection and subjected to DNA microarray analysis 1 h after a challenge dose of amphetamine.
  
  
  RESULTS
  A large number of genes with differential expression between high and low responders were identified, with no overlap between brain regions. Validation of these gene expression changes with real-time quantitative polymerase chain reaction demonstrated that the most robust and reproducible effects on gene expression were in the CA1 region of the hippocampus. Interestingly, many of the validated genes in CA1 are members of the cAMP response element (CRE) family and targets of the glucocorticoid receptor (GR) and myocyte enhancer factor 2 (Mef2) transcription factors.
  
  
  CONCLUSIONS
  We hypothesize that CRE, Mef2, and GR signaling form a transcription regulating network, which underlies differential amphetamine sensitivity, and therefore, may play an important role in susceptibility to psychosis.
authors.affiliation: Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research (LACDR) & Leiden University Medical Center, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. datson_n@lacdr.leidenuniv.nl
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Datson
authors.forename: Niels
authors.initials: N
authors.lastname: Speksnijder
authors.forename: Inge E M
authors.initials: IE
authors.lastname: de Jong
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Steenbergen
authors.forename: Kenneth
authors.initials: K
authors.lastname: Vielsted Christensen
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Potempa
authors.forename: Jan
authors.initials: J
authors.lastname: Torleif Pedersen
authors.forename: Jan
authors.initials: J
authors.lastname: Egebjerg
authors.forename: Pekka
authors.initials: P
authors.lastname: Kallunki
authors.forename: Erik B
authors.initials: EB
authors.lastname: Nielsen
authors.forename: E Ronald
authors.initials: ER
authors.lastname: de Kloet
authors.forename: Michael
authors.initials: M
authors.lastname: Didriksen
mesh_terms: D000661:Amphetamine / Q000009:adverse effects* / Q000493:pharmacokinetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D059647:Gene-Environment Interaction; D017781:Genes, Immediate-Early / Q000187:drug effects; D061346:Laser Capture Microdissection; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011605:Psychoses, Substance-Induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000661:Amphetamine