The Potential Antidepressant Action of Duloxetine Co-Administered with the TAAR1 Receptor Agonist SEP-363856 in Mice

Abstract

Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression.

Keywords: SEP-363856; antidepressant-like effect; co-administration; depression; duloxetine.

Figure 1

Effects of duloxetine, SEP-856, and their co-administration on the FST in ICR mice. (A) Effects of duloxetine (3, 5, 7.5, and 10 mg/kg, p.o.) on behavioral despair in the FST 60 min after administration. (B) Effects of SEP-856 (0.1, 0.3, 1, 3, and 10 mg/kg, p.o.) on behavioral despair in the FST 60 min after administration. (C) Effects of co-administration of duloxetine (3, 5, 7.5, and 10 mg/kg, p.o.) and SEP-856 (0.1 mg/kg, p.o.) on behavioral despair in the FST 60 after administration. Values are expressed as the mean ± SEM. from 4–8 mice and were analyzed using two-way ANOVA followed by Bonferroni’s post hoc test. * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001 vs. vehicle. DLX, duloxetine.

Figure 2

Effects of duloxetine, SEP-856, and their co-administration on the TST in ICR mice. (A) Effects of duloxetine (3, 5, 7.5, and 10 mg/kg, p.o.) on behavioral despair in the TST 60 min after administration. (B) Effects of SEP-856 (0.1, 0.3, 1, 3, and 10 mg/kg, p.o.) on behavioral despair in the TST 60 min after administration. (C) Effects of co-administration of duloxetine (3, 5, 7.5, and 10 mg/kg, p.o.) and SEP-856 (0.1 mg/kg, p.o.) on behavioral despair in the TST 60 min after administration. Values are expressed as the mean ± SEM. from 4–8 mice and were analyzed using two-way ANOVA followed by Bonferroni’s post-hoc test. * p < 0.05, ** p < 0.01, and **** p < 0.0001 vs. vehicle. DLX, duloxetine.

Figure 3

Effects of administration of duloxetine (3, 5, 7.5, and 10 mg/kg) and SEP-856 (0.1 mg/kg) on the locomotor activity of ICR mice. The test was performed 60 min after administration. Values are expressed as the mean ± SEM. from 8 mice and were analyzed using repeated-measures ANOVA followed by Bonferroni’s multiple comparisons test. DLX, duloxetine.

Figure 4

Effects of duloxetine (15 mg/kg), SEP-856 (15 mg/kg), and their co-administration on the sucrose preference in the CUMS model of depression in ICR mice. Values are expressed as the means ± SEM from 5–7 mice and were analyzed by two-way ANOVA followed by Bonferroni’s multiple comparisons test. **** p < 0.0001 vs. NS-Veh; # p < 0.05, ## p < 0.01 vs. CUMS-Veh. NS, non-stressed; CUMS, chronic unpredictable mild stress. DLX, duloxetine.