Figure 1.
Antidepressant-like effects of imipramine and dextromethorphan in the forced swim test in mice.
Imipramine (0–20 mg/kg, i.p.) significantly decreased immobility time (A), but had no significant effects on locomotor activity (B). Dextromethorphan (0–30 mg/kg, i.p.) significantly decreased immobility time (C), and significantly increased locomotor activity (D). However, there was no correlation between dextromethorphan (30 mg/kg)-induced locomotor stimulatory effects and decreased immobility times (E). Data shown are expressed as mean ± S.E.M. *P<0.05, **P<0.01, ***P<0.001, compared with the saline-treated group; one-way ANOVA followed by post-hoc Dunnett's tests. Pearson's r correlation test for correlation analysis. IM, imipramine. DM, dextromethorphan.
Figure 2.
Attenuation of the antidepressant-like effects of dextromethorphan, but not imipramine, by σ1 receptor antagonism.
Pretreatment with the σ1 receptor antagonist BD1063 (10 mg/kg, i.p.) prevented the dextromethorphan (30 mg/kg, i.p.)-induced decrease in immobility time (A). BD1047 (10 mg/kg, i.p.) pretreatment also produced a noticeable, albeit not statistically significant, trend toward the prevention of the decreased immobility time induced by dextromethorphan (B). In contrast, the antidepressant-like effect of imipramine (20 mg/kg, i.p.) in the forced swim test was not significantly prevented by BD1063 pretreatment (C). Data shown are expressed as mean ± S.E.M. *P<0.05, ***P<0.001, compared with the saline-treated group; #P<0.05, compared with the dextromethorphan-treated group; one-way ANOVA followed by post-hoc Tukey's tests. IM, imipramine. DM, dextromethorphan.
Figure 3.
Competitive antagonism of the behavioral effects of dextromethorphan by BD1063.
A single dose of BD1063 (10 mg/kg, i.p.) pretreatment shifted the dextromethorphan (0–50 mg/kg, i.p.) dose response curve to the right in the forced swim test (A), and blocked the dextromethorphan-induced stimulatory effect in the locomotor study (B). Data shown are expressed as mean ± S.E.M. *P<0.05, **P<0.01 compared with the dextromethorphan (30 mg/kg, i.p.)-treated group; one-way ANOVA followed by post-hoc Tukey's tests. DM, dextromethorphan.
Figure 4.
Potentiation of the antidepressant-like effects of dextromethorphan by quinidine.
A single dose of the CYP2D6 inhibitor quinidine (30 mg/kg, i.p.) administered concomitantly with dextromethorphan (0–30 mg/kg, i.p.) significantly potentiated the decrease in immobility time for dextromethorphan at 10 mg/kg (A). In contrast, in the locomotor study, dextromethorphan in combination with quinidine had no stimulatory effects (B). Data shown are expressed as mean ± S.E.M. ***P<0.001, compared with the saline-treated group; one-way ANOVA followed by post-hoc Tukey's tests. QND, quinidine. DM, dextromethorphan.
Table 1.
Binding parameters for σ1 receptors in the absence and presence of dextromethorphan.