title: Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel.
abstract: BACKGROUND
  Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice.
  
  
  METHODS
  Mice from 39 BXD strains acquired cocaine IVSA (0.56 mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032-1.8 mg/kg/infusion). We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant quantitative trait loci (QTL) on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-naïve mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome-wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use.
  
  
  CONCLUSIONS
  These data provide novel candidate genes underlying cocaine IVSA in mice and suggest mechanisms driving human cocaine use.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA. price.dickson@jax.org.
authors.forename: Price E
authors.initials: PE
authors.lastname: Dickson
authors.affiliation: Department of Psychology, University of Memphis, Memphis, TN, 38152, USA.
authors.forename: Mellessa M
authors.initials: MM
authors.lastname: Miller
authors.affiliation: Department of Psychology, University of Memphis, Memphis, TN, 38152, USA.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Calton
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bubier
authors.affiliation: Department of Psychology, University of Memphis, Memphis, TN, 38152, USA.
authors.forename: Melloni N
authors.initials: MN
authors.lastname: Cook
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldowitz
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.affiliation: Department of Psychology, University of Memphis, Memphis, TN, 38152, USA. gmittleman@bsu.edu.|Department of Psychological Science, Ball State University, North Quad (NQ), room 104, Muncie, IN, 47306, USA. gmittleman@bsu.edu.
authors.forename: Guy
authors.initials: G
authors.lastname: Mittleman
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D040641:Quantitative Trait Loci / Q000187:drug effects / Q000235:genetics; D012646:Self Administration; D049490:Systems Biology / Q000379:methods
chemical_list: D003042:Cocaine
keywords: Addiction; Aplp1; Cocaine sensitization; Cyfip2; Fam53b; Genetic correlation; Light dark box; Open field; QTL; eQTL