title: Involvement of glial cell line-derived neurotrophic factor in inhibitory effects of a hydrophobic dipeptide Leu-Ile on morphine-induced sensitization and rewarding effects.
abstract: There are few efficacious medications for drug dependence at present. We have previously demonstrated that Leu-Ile, which induces the expression of not only tumor necrosis factor-alpha (TNF-alpha) but also glial cell line-derived neurotrophic factor (GDNF), inhibits methamphetamine (METH) and morphine (MOR)-induced sensitization and rewarding effects by regulating extracellular dopamine levels via the induction of TNF-alpha expression, and indicated the potential of Leu-Ile as a novel therapeutic agent for METH and MOR-induced dependence. In the present study, we investigated the involvement of GDNF in inhibitory effects of Leu-Ile on MOR-induced sensitization and rewarding effects. Repeated treatment with MOR for 9 days, which results in an enhancement of the locomotor-stimulating effects (sensitization) of MOR, increased GDNF levels in the nucleus accumbens compared with those in saline-treated mice. Repeated pre-treatment with Leu-Ile for 9 days potentiated the MOR-induced increase in GDNF levels. MOR at a low dose (3mg/kg) produced place preference in GDNF heterozygous knockout (GDNF-(+/-)) mice, but not in littermate GDNF-(+/+) mice. No inhibitory effect of Leu-Ile on MOR-induced place preference was observed in GDNF-(+/-) mice. These results suggest that GDNF is involved in the inhibitory effects of Leu-Ile on MOR-induced sensitization and rewarding effects.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
authors.forename: Minae
authors.initials: M
authors.lastname: Niwa
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Liya
authors.initials: L
authors.lastname: Shen
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D012201:Reward
chemical_list: D004151:Dipeptides; D051098:Glial Cell Line-Derived Neurotrophic Factors; D009294:Narcotics; C492946:leucyl-isoleucyl; D009020:Morphine