title: Dissociable role of tumor necrosis factor alpha gene deletion in methamphetamine self-administration and cue-induced relapsing behavior in mice.
abstract: BACKGROUND
  During the development of addiction, addictive drugs induce transient and long-lasting changes in the brain including expression of endogenous molecules and alteration of morphological structure. Of the altered endogenous molecules, some facilitate but others slow the development of drug addiction. Previously, we have reported that tumor necrosis factor alpha (TNF-α) is a critical molecule among endogenous anti-addictive modulators using animal models of drug-conditioned place preference and drug discrimination.
  
  
  OBJECTIVE
  Does targeted deletion of the TNF-α gene in mice affect methamphetamine (METH) self-administration, motivation to self-administer METH, cue-induced reinstatement of METH-seeking behavior, and food reinforcement or seeking behavior?
  
  
  METHODS
  Both METH self-administration and reinstatement of drug-seeking behavior and food self-delivery and food-seeking behavior were measured in TNF-α (-/-) and wild-type mice.
  
  
  RESULTS
  There were an upward shift of dose responses to METH self-administration under a fixed ratio schedule of reinforcement and higher breaking points under a progressive ratio schedule of reinforcement in TNF-α knockout (TNF-α (-/-)) mice as compared with wild-type mice. There was no significant difference in cue-induced reinstatement of METH-seeking behavior, food-maintained operant behavior, motivation to natural food, and cue-induced food-seeking behavior between TNF-α (-/-) and wild-type mice.
  
  
  CONCLUSIONS
  TNF-α affects METH self-administration and motivation to self-administer METH but contributes to neither METH-associated cue-induced relapsing behavior nor food reward and food-seeking behavior. TNF-α may be explored for use as a diagnostic biomarker for the early stage of drug addiction.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya 466-8560, Japan.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Yan
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Takenao
authors.initials: T
authors.lastname: Koseki
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003216:Conditioning, Operant; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior; D017353:Gene Deletion; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation; D012055:Reinforcement Schedule; D012646:Self Administration; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000697:Central Nervous System Stimulants; D014409:Tumor Necrosis Factor-alpha; D008694:Methamphetamine