7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine.
BACKGROUND
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 × 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.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan.
Qian
Q
Ren
Ji-Chun
JC
Zhang
Min
M
Ma
Yuko
Y
Fujita
Jin
J
Wu
Kenji
K
Hashimoto
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004298:Dopamine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000517:prevention & control* / Q000523:psychology; D020813:Receptor, trkB / Q000819:agonists*
C485383:6,7-dihydroxyflavone; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D047309:Flavones; D005419:Flavonoids; C043561:chrysin; D008694:Methamphetamine; D020813:Receptor, trkB; D004298:Dopamine