Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models

Abstract

Clinical evidences show sex differences in risk of developing depressive disorders as well as effect of antidepressants in depression treatment. However, whether such a sex-dependent risk of depression and efficacy of antidepressants is dependent on endogenous estrogen level remain elusive. The aim of this study is to explore the molecular mechanisms of sex differences in antidepressant duloxetine. In the present study, we used genetic knockout or overexpression estrogen-synthesizing enzyme aromatase (Ar) gene as models for endogenous estrogen deficiency and elevation endogenous estrogen, respectively, to examine the anti-depressive efficacy of duloxetine in males and females by force swimming test (FST). We also measured the sex-specific effect of duloxetine on dopamine and serotonin (5-HT) metabolisms in frontal cortex and hippocampus (HPC). Elevation of brain endogenous estrogen in male and female mice showed a reduction of immobility time in FST compared to control mice. Estrogen deficiency in females showed poor response to duloxetine treatment compared to sex-matched wildtype (WT) or aromatase transgenic mice. In contrast, male mice with estrogen deficiency showed same anti-depressive response to duloxetine treatments as aromatase transgenic mice. Our data showed that the sex different effect of endogenous estrogen on duloxetine-induced anti-depressive behavioral change is associated with brain region-specific changes of dopamine (DA) and 5-HT system. Endogenous estrogen exerts antidepressant effects in both males and females. Lacking of endogenous estrogen reduced antidepressive effect of duloxetine in females only. The endogenous estrogen level alters 5-HT system in female mainly, while both DA and 5-HT metabolisms were regulated by endogenous estrogen levels after duloxetine administration.

Keywords: depressants; duloxetine; estrogen; mice; sex difference.

Figure 1

Immobility time in the force swimming test (FST) of three genotype in both female and male mice treated by duloxetine. The immobility time in the FST of three genotype in female mice (A) and male mice (B) treated by duloxetine. ^##Indicates P < 0.01 compared to vehicle-treated, *indicate P < 0.05 and **P < 0.01 compared to wildtype (WT) mice mice. n = 6–7 mice/group.

Figure 2

Duloxetine do not affect locomotor activity in both male and female mice in all three genotypes. The distance moved in the spontaneous locomotor activity of three genotype in female mice (A) and male mice (B) treated by duloxetine showed no differences in all three genotype treated by vehicle or duloxetine. n = 6–7 mice/group.

Figure 3

Sex differences in the effect of endogenous estrogen on dopamine (DA) and serotonin (5-HT) turnover rates in the prefrontal cortex (PFC) and hippocampus (HPC). The effect of endogenous estrogen on DA and 5-HT index of three genotype in female PFC (A), female HPC (B), male PFC (C) and male HPC (D). *Indicate P < 0.05 and **P < 0.01 compared to WT mice. n = 6–7 mice/group.

Figure 4

Sex differences in the effect of duloxetine on DA and 5-HT index in the PFC and HPC. The effect of duloxetine on DA and 5-HT index of three genotype in female PFC (A), female HPC (B), male PFC (C) and male HPC (D). ^#Indicates P < 0.05 and ^##P < 0.01 compared to vehicle-treated, *indicate P < 0.05 and **P < 0.01 compared to WT mice. n = 6–7 mice/group.