title: Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period.
abstract: BACKGROUND
  Netrin-1 guidance cues contribute to amphetamine-induced plasticity of the adult mesocorticolimbic dopamine system in rodents. The netrin-1 receptor, deleted in colorectal cancer (DCC), is upregulated by repeated amphetamine treatment selectively in the ventral tegmental area (VTA) of adult rats and wild-type mice. Furthermore, adult dcc heterozygous mice fail to show amphetamine-induced increases in VTA DCC expression and do not develop sensitization to this drug.
  
  
  OBJECTIVE
  The effects of netrin-1 receptor signaling on mesocorticolimbic dopamine system function change across development. However, the effects of AMPH on DCC receptor regulation and behavioral sensitization before puberty have not been determined. Here we examined whether (1) repeated amphetamine treatment would also alter DCC expression in juvenile rats and wild-type mice, and (2) dcc heterozygotes treated with amphetamine during the juvenile period (PND 22-32) would develop behavioral sensitization to this drug.
  
  
  RESULTS
  Repeated amphetamine downregulates DCC expression selectively in the VTA of juvenile rodents. Moreover, the behavioral phenotype of adult dcc heterozygous mice is not present before puberty and is abolished by amphetamine treatment during the juvenile period. Remarkably, adult dcc heterozygotes pretreated with amphetamine as juveniles no longer exhibit reduced DCC expression in the VTA compared to wild-type controls.
  
  
  CONCLUSIONS
  Our results indicate that netrin-1 receptor signaling may be a key factor in determining individual differences in vulnerability to the behaviorally sensitizing effects of amphetamine at different ages. Moreover, they suggest that the juvenile period marks a window of vulnerability during which exposure to stimulant drugs can reverse the behavioral phenotype of adult dcc heterozygous mice.
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
authors.forename: Leora
authors.initials: L
authors.lastname: Yetnikoff
authors.forename: Anne
authors.initials: A
authors.lastname: Almey
authors.forename: Andreas
authors.initials: A
authors.lastname: Arvanitogiannis
authors.forename: Cecilia
authors.initials: C
authors.lastname: Flores
mesh_terms: D000375:Aging / Q000187:drug effects / Q000523:psychology*; D000661:Amphetamine / Q000009:adverse effects*; D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D000075389:DCC Receptor; D015536:Down-Regulation; D059647:Gene-Environment Interaction; D006579:Heterozygote; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000075386:Netrin Receptors; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000661:Amphetamine