title: ΔFosB enhances the rewarding effects of cocaine while reducing the pro-depressive effects of the kappa-opioid receptor agonist U50488.
abstract: BACKGROUND
  Elevated expression of the transcription factor ΔFosB accompanies repeated exposure to drugs of abuse, particularly in brain areas associated with reward and motivation (e.g., nucleus accumbens). The persistent effects of ΔFosB on target genes might play an important role in the development and expression of behavioral adaptations that characterize addiction. This study examines how ΔFosB influences the responsiveness of the brain reward system to rewarding and aversive drugs.
  
  
  METHODS
  We used the intracranial self-stimulation paradigm to assess the effects of cocaine in transgenic mice with inducible overexpression of ΔFosB in striatal regions (including nucleus accumbens and dorsal striatum). Mice implanted with lateral hypothalamic stimulating electrodes were trained with the "rate-frequency" procedure for intracranial self-stimulation to determine the frequency at which stimulation becomes rewarding (threshold).
  
  
  RESULTS
  A dose-effect analysis of cocaine effects revealed that mice overexpressing ΔFosB show increased sensitivity to the rewarding (threshold-lowering) effects of the drug, compared with littermate control subjects. Interestingly, mice overexpressing ΔFosB were also less sensitive to the pro-depressive (threshold-elevating) effects of U50488, a kappa-opioid agonist known to induce dysphoria and stress-like effects in rodents.
  
  
  CONCLUSIONS
  These data suggest that induction of ΔFosB in striatal regions has two important behavioral consequences-increased sensitivity to drug reward, and reduced sensitivity to aversion-producing a complex phenotype that shows signs of vulnerability to addiction as well as resilience to stress.
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Muschamp
authors.forename: Christina L
authors.initials: CL
authors.lastname: Nemeth
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage*; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001703:Biophysics; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000502:physiology; D008297:Male; D008474:Medial Forebrain Bundle / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012201:Reward; D012653:Self Stimulation
chemical_list: D000779:Anesthetics, Local; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D017473:Receptors, Opioid, kappa; C116587:kappa(1) opioid receptor; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D010751:Phosphopyruvate Hydratase; D003042:Cocaine