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, 13 (5), 531-540

7,8-Dihydroxyflavone, a Tropomyosin-Kinase Related Receptor B Agonist, Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress

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7,8-Dihydroxyflavone, a Tropomyosin-Kinase Related Receptor B Agonist, Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress

Hsin-An Chang et al. Psychiatry Investig.

Abstract

Objective: Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), play important roles in treating depression. In this experiment, we examined whether 7,8-dihydroxyflavone, a novel potent TrkB agonist, could reverse the behavioral and biochemical abnormalities induced by the chronic mild stress (CMS) paradigm in rats.

Methods: SD rats were exposed to a battery of stressors for 56 days. 7,8-dihydroxyflavone (5 and 20 mg/kg) were administered intraperitoneally during the last 28 days of the CMS paradigm. Rats were tested in sucrose consumption test (SCT), forced-swimming test (FST) and elevated T-maze (ETM). Serum corticosterone levels and hippocampal BDNF levels of the rats were measured.

Results: Four-week CMS on the rats induced their depression-like behavior in SCT. The CMS-reduced sucrose consumption was reversed starting from 7 days after the 7,8-dihydroxyflavone (20 mg/kg) treatment and remained across the subsequent treatment regime. 7,8-dihydroxyflavone, when given at 5 mg/kg for 3 weeks, reduced the immobility time in the FST in the CMS-subjected rats. Additionally, the 4-week treatment with 7,8-dihydroxyflavone (20 mg/kg) attenuated the CMS-induced increase in anxiety-like behavior in the ETM. For the CMS-subjected rats, 7,8-dihydroxyflavone treatment dose-dependently reduced their serum corticosterone levels but increased their hippocampal BDNF levels only at 5 mg/kg.

Conclusion: 7,8-dihydroxyflavone was beneficial for both depression and anxiety-like behaviors, and may exert fast-onset antidepressant effects. This provides a new insight into the pharmacological management of depression.

Keywords: Anxiety; BDNF; Chronic mild stress; Depression; TrkB agonist.

Figures

Figure 1
Figure 1. Behavioral effects of the 4 week CMS. A: The CMS protocol involved subjecting animals to 8 week CMS. After 4 week CMS, animals were treated with 7,8-DHF or vehicle injection. During 8 week CMS period, sucrose consumption test were carried out once a week, Locomotion activity tests in week 0, 4, and 6, Forced swimming test in week 7 and elevated T-maze in week 8. B: The effect of 4 week CMS on body weight gain (C) Consumption of 2 % sucrose solution in rats exposure to 4 week CMS versus control rats. D: Body weight gain in the CMS rats and control rats treated with vehicle, 5 and 20 mg/kg 7,8-DHF for three weeks. Values are presented as mean+SEM. *p<0.05, **p<0.01, ***p<0.001, the CMS group vs. control group. #p<0.05, ##p<0.01, ###p<0.001, compared within the CMS or control group.
Figure 2
Figure 2. A: Consumption of 2% sucrose solution in the CMS rats and control rats treated with vehicle (n=11), 5 mg/kg (n=9) and 20 mg/kg (n=8) 7,8-DHF for one week and (B) for three weeks. Values are presented as mean+SEM. *p<0.05, **p<0.01, ***p<0.001, the CMS group vs. control group. #p<0.05, ##p<0.01, ###p<0.001, compared within the CMS or control group.
Figure 3
Figure 3. A: Locomotor activities in the CMS rats and control rats treated with vehicle and different 7,8-DHF dosages for 2 weeks. B: Immobility, C: swimming, and (D) climbing time in FST in the CMS rats and control rats treated with vehicle and different 7,8-DHF dosages for 3 weeks. The data represent the mean+SEM. *p<0.05, the CMS group vs. control group. ##p<0.01, compared within the CMS or control group.
Figure 4
Figure 4. A: The latencies to leave the enclosed arm and (B) the open arm were measured from the CMS rats and control rats treated with vehicle and different 7,8-DHF dosages for 4 weeks. Result are presented as mean+SEM. *p<0.05, the CMS group vs. control group. #p<0.05, compared within the CMS or control group.
Figure 5
Figure 5. A: The BDNF protein level in hippocampus and (B) serum corticosterone level in the CMS rats and control rats treated with vehicle and different 7,8-DHF dosages for 3 weeks. Data represent mean+SEM. *p<0.05, **p<0.01, ***p<0.001, the CMS group vs. control group. #p<0.05, ##p<0.01, compared within the CMS or control group.

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