title: Cocaine self-administration behaviors in ClockΔ19 mice.
abstract: BACKGROUND
  A key role has been identified for the circadian locomotor output cycles kaput (Clock) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the Clock gene (ClockΔ19 mice) exhibit increased cocaine-induced conditioned place preference, reduced anxiety- and depression-like behavior, increased sensitivity to intracranial self-stimulation, and increased dopaminergic cell activity in the ventral tegmental area.
  
  
  OBJECTIVE
  We sought to determine if this hyperhedonic phenotype extends to cocaine self-administration and measures of motivation.
  
  
  METHODS
  Two separate serial testing procedures were carried out (n = 7-10/genotype/schedule). Testing began with acquisition of sucrose pellet self-administration, implantation of intravenous catheter, acquisition of cocaine self-administration, and dose-response testing (fixed ratio or progressive ratio). To evaluate diurnal variations in acquisition behavior, these sessions occurred at Zeitgeber 2 (ZT2) or ZT14.
  
  
  RESULTS
  WT and ClockΔ19 mice exhibited similar learning and readily acquired food self-administration at both ZT2 and ZT14. However, only ClockΔ19 mice acquired cocaine self-administration at ZT2. A greater percentage of ClockΔ19 mice reached acquisition criteria at ZT2 and ZT14. ClockΔ19 mice self-administered more cocaine than WT mice. Using fixed ratio and progressive ratio schedules of reinforcement dose-response paradigms, we found that cocaine is a more efficacious reinforcer in ClockΔ19 mice than in WT mice.
  
  
  CONCLUSIONS
  Our results demonstrate that the Clock gene plays an important role in cocaine reinforcement and that decreased CLOCK function increases vulnerability for cocaine use.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, 450 Technology Dr. (BSPII Ste 233), Pittsburgh, PA 15219, USA. ozburna@gmail.com
authors.forename: Angela Renee
authors.initials: AR
authors.lastname: Ozburn
authors.forename: Erin Beth
authors.initials: EB
authors.lastname: Larson
authors.forename: David W
authors.initials: DW
authors.lastname: Self
authors.forename: Colleen A
authors.initials: CA
authors.lastname: McClung
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D056926:CLOCK Proteins / Q000235:genetics* / Q000502:physiology; D057906:Circadian Clocks / Q000235:genetics; D003042:Cocaine / Q000008:administration & dosage* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009154:Mutation; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D056926:CLOCK Proteins; C538944:Clock protein, mouse; D003042:Cocaine