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Major depressive disorder (MDD) is a severe mental disorder with a high disability rate worldwide. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are the most common agents for antidepressant use. SSRIs and SNRIs are believed to achieve antidepressant effects through the activation of serotonergic or noradrenergic systems. However, whether the dopaminergic system is involved remains unclear. In our study, a genetically encoded dopamine sensor and in vivo fiber photometry recordings were used to measure the dopamine concentrations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute intraperitoneal injection of SSRIs or SNRIs. Combined with the behavioral tests, we found that SNRIs increased dopamine concentrations in both the mPFC and the NAc and showed faster antidepressant effects than SSRIs. To verify the enhanced dopamine levels induce the faster antidepressant effects of SNRIs, we employed dopamine receptor antagonists to specifically block the dopaminergic function. The results showed that the faster antidepressant effects of SNRIs were weakened by the dopamine receptor antagonists. Altogether, our study reveals that SNRIs achieve faster antidepressant effects than SSRIs by elevating the dopamine concentrations in the mPFC and the NAc. Our work proposes further mechanisms for the first-line antidepressants, which provides more basis for clinical treatments

Figure 1. Effects of different SNRIs and SSRIs on dopamine concentration in the mPFC.

The study is aimed to explore the effects of the dopaminergic system on selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). In this study, to verify whether SNRIs or SSRIs enhance DA levels, in vivo fiber photometry recordings with the fluorescent dopamine sensor were used to measure the DA concentrations. To further investigate the correlation between the dopaminergic function and the faster antidepressant effects of SNRIs, the authors employed pharmacological approaches to specifically block the dopaminergic function during the behavioral tests. Overall, the work investigates a novel mechanism of the faster antidepressant effects of SNRIs and provides a new perspective for the clinical treatment of depression.

 
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