PMID- 23934209 OWN - NLM STAT- MEDLINE DCOM- 20140818 LR - 20211021 IS - 1432-2072 (Electronic) IS - 0033-3158 (Linking) VI - 231 IP - 1 DP - 2014 Jan TI - 7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine. PG - 159-66 LID - 10.1007/s00213-013-3221-7 [doi] AB - RATIONALE: It is widely recognized that methamphetamine (METH) induces behavioral abnormalities and dopaminergic neurotoxicity in the brain. Several lines of evidence suggest a role for brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), in METH-induced behavioral abnormalities. OBJECTIVE: In this study, we examined whether 7,8-dihydroxyflavone (7,8-DHF), a novel potent TrkB agonist, could attenuate behavioral abnormalities and dopaminergic neurotoxicity in mice after administration of METH. RESULTS: Pretreatment with 7,8-DHF (3.0, 10, or 30 mg/kg), but not the inactive TrkB compound, 5,7-dihydroxyflavone (5,7-DHF) (30 mg/kg), attenuated hyperlocomotion in mice after a single administration of METH (3.0 mg/kg), in a dose-dependent manner. The development of behavioral sensitization after repeated administration of METH (3.0 mg/kg/day, once daily for 5 days) was significantly attenuated by pretreatment with 7,8-DHF (10 mg/kg). Furthermore, pretreatment and subsequent administration of 7,8-DHF (10 mg/kg) attenuated the reduction of dopamine transporter (DAT) in the striatum after repeated administration of METH (3.0 mg/kg x 3 at 3-hourly intervals). Treatment with ANA-12 (0.5 mg/kg), a potent TrkB antagonist, blocked the protective effects of 7,8-DHF on the METH-induced reduction of DAT in the striatum. Moreover, 7,8-DHF attenuated microglial activation in the striatum after repeated administration of METH. CONCLUSIONS: These findings suggest that 7,8-DHF can ameliorate behavioral abnormalities as well as dopaminergic neurotoxicity in mice after administration of METH. It is likely, therefore, that TrkB agonists such as 7,8-DHF may prove to be potential therapeutic drugs for several symptoms associated with METH abuse in humans. FAU - Ren, Qian AU - Ren Q AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan. FAU - Zhang, Ji-Chun AU - Zhang JC FAU - Ma, Min AU - Ma M FAU - Fujita, Yuko AU - Fujita Y FAU - Wu, Jin AU - Wu J FAU - Hashimoto, Kenji AU - Hashimoto K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130810 PL - Germany TA - Psychopharmacology (Berl) JT - Psychopharmacology JID - 7608025 RN - 0 (6,7-dihydroxyflavone) RN - 0 (Central Nervous System Stimulants) RN - 0 (Dopamine Plasma Membrane Transport Proteins) RN - 0 (Flavones) RN - 0 (Flavonoids) RN - 3CN01F5ZJ5 (chrysin) RN - 44RAL3456C (Methamphetamine) RN - EC 2.7.10.1 (Receptor, trkB) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Behavior, Animal/*drug effects MH - Central Nervous System Stimulants/antagonists & inhibitors/*toxicity MH - Dopamine/physiology MH - Dopamine Plasma Membrane Transport Proteins/metabolism MH - Flavones/*pharmacology MH - Flavonoids/pharmacology MH - Immunohistochemistry MH - Male MH - Methamphetamine/antagonists & inhibitors/*toxicity MH - Mice MH - Mice, Inbred BALB C MH - Motor Activity/drug effects MH - Neostriatum/drug effects MH - Neurotoxicity Syndromes/*prevention & control/psychology MH - Receptor, trkB/*agonists EDAT- 2013/08/13 06:00 MHDA- 2014/08/19 06:00 CRDT- 2013/08/13 06:00 PHST- 2013/02/23 00:00 [received] PHST- 2013/07/18 00:00 [accepted] PHST- 2013/08/13 06:00 [entrez] PHST- 2013/08/13 06:00 [pubmed] PHST- 2014/08/19 06:00 [medline] AID - 10.1007/s00213-013-3221-7 [doi] PST - ppublish SO - Psychopharmacology (Berl). 2014 Jan;231(1):159-66. doi: 10.1007/s00213-013-3221-7. Epub 2013 Aug 10.