7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine

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. 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. 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. 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.