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.
Highlights
Major depressive disorder (MDD) is reported to be one of the most common mental health challenges in the world (Mitchell et al, 2011)
At age of 2–3 months, vehicle treated female Thy1-Ar mice spent less immobile time than that of WT mice, while a similar effect of brain estrogen on force swimming test (FST) in male Thy1-Ar mice was observed (Figures 1A,B). Both male and female Ar+/− mice with endogenous estrogen deficiency showed a trend of increasing depressive behavior as measured by immobility compared to sex-matched WT mice, while the changes did not reach statistical significance
When we compare the effect of duloxetine on different genotypes in females, our data showed no significant change between female Ar+/− and female Thy1-Ar and WT, a trend of increasing immobile time was found in female Ar+/− mice (Figure 1A)
Summary
Major depressive disorder (MDD) is reported to be one of the most common mental health challenges in the world (Mitchell et al, 2011). Depression in women are associated with an increased sensitivity to changes in the hormonal milieu, such as the luteal phase of cycles, the postpartum period and during the menopause transition (Young et al, 2000; Maartens et al, 2002; Payne, 2003). Some research showed that female with low level of estrogen is associated with the higher risk of MDD (Young et al, 2000; Maartens et al, 2002; Payne, 2003), and estrogen treatment can treat depression in perimenopausal women, improve the happiness of menopause women (Schneider et al, 1997; Schmidt, 2005a,b), alleviate depressive symptoms in females (Sherwin, 1994), and manage hormonal-related depression in females (Soares, 2014, 2017). While estrogenic functions in regulating behavioral states such as mood and cognition have been relatively well documented in both human and animal studies, the effectiveness of estrogen therapy in depression is still remained controversial as some clinical studies show no effects of estrogen replacement therapy on reversing depressive-like symptoms for postmenopausal women (Arnold et al, 2004; Morrison et al, 2004; Goldstein et al, 2005; Pefanco et al, 2007; Martel et al, 2009)
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