title: Effects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine.
abstract: Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway plays a role in behavioral abnormalities observed after administration of psychostimulants, such as methamphetamine (METH). This study was undertaken to examine whether the potent TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) could improve prepulse inhibition (PPI) deficits in mice seen after a single dose of METH. Treatment with 7,8-DHF (3.0, 10 or 30 mg/kg) improved PPI deficits in mice associated with exposure to METH (3.0 mg/kg), in a dose dependent manner. Furthermore, co-administration of ANA-12 (0.5 mg/kg), a TrkB antagonist, significantly blocked the effects of 7,8-DHF (30 mg/kg) on METH-induced PPI deficits. In contrast, administration of 5,7-dihydroxyflavone (5,7-DHF: 30 mg/kg), an inactive TrkB ligand, did not affect METH-induced PPI deficits in mice. An in vivo microdialysis study in conscious mice showed that 7,8-DHF (30 mg/kg) significantly attenuated increased dopamine release in the striatum, after METH administration (3 mg/kg). This study suggests that 7,8-DHF can improve PPI deficits in these mice, through the inhibition of METH-induced dopamine release. Therefore, it is likely that TrkB agonists, such as 7,8-DHF, may constitute a novel class of therapeutic drugs for neuropsychiatric diseases such as METH-use disorder and schizophrenia.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.forename: Ji-Chun
authors.initials: JC
authors.lastname: Zhang
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D047309:Flavones / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D017551:Microdialysis; D020813:Receptor, trkB / Q000037:antagonists & inhibitors*
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D008694:Methamphetamine; D020813:Receptor, trkB