(A) Forced swim test with 4'-DMA-7,8-DHF and 7,8-DHF compounds. Male C57BL/6J mice (8 mice/group) were orally administrated by gavage with 5 mg/kg 4'-DMA-7,8-DHF and 7,8-DHF and vehicle solvent saline for 21 days, and subjected to a forced swim test (6 min, immobility recorded in the last 4 min). Data are presented as mean ± SEM. Analysis of variance (ANOVA) revealed significant difference between vehicle and either 7,8-DHF or 4'-DMA-7,8-DHF (n=6, ***P<0.0001 vs vehicle). (B) TrkB but not TrkA is activated by 4'-DMA-7,8-DHF and 7,8-DHF in mouse brain. The brain lysates from above chronically treated mice were analyzed by immunoblotting with anti-p-TrkA 794 and p-TrkB 817. (C) Forced swim test with TrkB F616A knockin mice. Male TrkB knockin mice were given the regular drinking water or 1NMPP1 (25 μM) containing drinking water one day before we started to inject the drugs and sustained throughout the whole experiment. The indicated control (saline) and drugs were administrated for 5 days. Data are presented as mean ± SEM; Analysis of variance (ANOVA) revealed significant effect between vehicle and either 7,8-DHF (n=7 mice, **P<0.001) or 4'-DMA-7,8-DHF (**P<0.001) in TrkB KI mice. None of the drugs produced a significant change in 1NMPP1 treated TrkB KI mice (n=6 to 7 mice) as compared to control.