An inducer for glial cell line-derived neurotrophic factor and tumor necrosis factor-alpha protects against methamphetamine-induced rewarding effects and sensitization

Biol Psychiatry. 2007 Apr 1;61(7):890-901. doi: 10.1016/j.biopsych.2006.06.016. Epub 2006 Oct 13.


Background: There are few efficacious medications for drug dependence. We investigated the potential of Leu-Ile, which induces the expression of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-alpha (TNF-alpha), as a novel therapeutic agent for methamphetamine (METH)-induced dependence.

Methods: The levels of GDNF and TNF-alpha messenger RNA (mRNA) were determined by real-time reverse transcription polymerase chain reaction. Enzyme immunoassays and immunohistochemistry were employed to determine levels of these proteins. Effects of Leu-Ile on METH-induced rewarding effects and sensitization were investigated with conditioned place preference and locomotor activity tests. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were examined with an in vivo microdialysis and trititated thymidine ([(3)H]) DA uptake assay.

Results: Leu-Ile induced the expression of not only GDNF but also TNF-alpha. Pretreatment with Leu-Ile blocked the acquisition of METH-induced place preference and sensitization. Interestingly, post-treatment with Leu-Ile attenuated them even after their development. An inhibitory effect of Leu-Ile on METH-induced place preference was observed in neither GDNF heterozygous nor TNF-alpha knockout mice. Leu-Ile inhibited DA release in the nucleus accumbens and the decrease in synaptosomal DA uptake in the midbrain induced by repeated METH treatment.

Conclusions: These results suggest that Leu-Ile inhibits METH-induced rewarding effects and sensitization by regulating extracellular DA levels via the induction of GDNF and TNF-alpha expression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Central Nervous System Stimulants / administration & dosage*
  • Conditioning, Operant / drug effects*
  • Dipeptides / pharmacology*
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Enzyme Activation / drug effects
  • Gene Expression Regulation / drug effects*
  • Glial Cell Line-Derived Neurotrophic Factor / deficiency
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology
  • Male
  • Methamphetamine / administration & dosage*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Reward*
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • Central Nervous System Stimulants
  • Dipeptides
  • Glial Cell Line-Derived Neurotrophic Factor
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • leucyl-isoleucyl
  • Methamphetamine
  • Dopamine