title: Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats.
abstract: BACKGROUND
  Physical activity, and specifically exercise, has shown promise as an intervention for drug addiction; however, the exercise conditions that produce the most efficacious response, as well as its underlying mechanism, are unknown.
  
  
  OBJECTIVE
  In this study, we examined the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking and associated changes in prefrontal cortex (PFC) brain-derived neurotrophic factor (Bdnf) exon IV expression, a marker of epigenetic regulation implicated in cocaine relapse and known to be regulated by exercise.
  
  
  METHODS
  Cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure following extended access cocaine or saline self-administration (24-h/day, 4 discrete trials/h, 10 days, 1.5 mg/kg/infusion) and a 14-day abstinence period. During abstinence, rats had either locked or unlocked running wheel access for 1, 2, or 6 h/day. Bdnf exon IV expression was assessed using quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  Cocaine-seeking was highest under the locked wheel condition, and wheel running dose dependently attenuated this effect. Cocaine increased Bdnf exon IV expression, and wheel running dose dependently attenuated this increase, with complete blockade in rats given 6-h/day access. Notably, the efficacy of exercise was inversely associated with Bdnf exon IV expression, and both its efficacy and its effects on Bdnf exon IV expression were mimicked by treatment during abstinence with sodium butyrate, a histone deacetylase inhibitor that, like exercise, modulates gene transcription, including Bdnf exon IV expression.
  
  
  CONCLUSIONS
  Taken together, these results indicate that the efficacy of exercise is dose dependent and likely mediated through epigenetic regulation of PFC Bdnf.
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA, 22911, USA.
authors.forename: Alexis B
authors.initials: AB
authors.lastname: Peterson
authors.forename: Jean M
authors.initials: JM
authors.lastname: Abel
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Lynch
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics*; D020148:Butyric Acid / Q000627:therapeutic use; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000517:prevention & control; D003216:Conditioning, Operant / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects; D005081:Exercise Therapy; D005091:Exons / Q000235:genetics*; D005108:Extinction, Psychological; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D012420:Running / Q000502:physiology*; D012646:Self Administration; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D020148:Butyric Acid; D003042:Cocaine