Mental disorders are caused by contributing to genetic and environmental factors. We here show that deficiency of a genetic risk factor D2LR, an isoform of dopamine D2 receptor (D2R) causes psychosocial stress vulnerability through a serotonin (5-hydroxytryptamine, 5-HT) receptor 5-HT1AR dysfunction on serotonergic neurons in mouse brain. Exposure to forced swim (FS) stress significantly increases anxiety- and depressive-like behaviors in D2LR knockout (D2LR-KO) male mice. 8-OH-DPAT a 5-HT1AR agonist, which mimics the effect of antidepressants, fails to response the stress-induced behaviors in D2LR-KO mice. In FS-stressed D2LR-KO mice, elevated 5-HT release in the medial prefrontal cortex (mPFC) and upregulation of 5-HT homeostasis related transcripts through Pet1 in the dorsal raphe nucleus (DRN) are observed. D2LR forms heteromer with 5-HT1AR in serotonergic neurons, and 5-HT1AR-activated G protein-activated inwardly rectifying potassium (GIRK) conductance is inhibited in D2LR-KO serotonergic neurons. Finally, we show that D2LR overexpression in serotonergic neurons of the raphe nucleus reduces the stress vulnerability in D2LR-KO mice. Taken together, the collapse of negative feedback control in D2LR/5-HT1A inhibitory G-protein-coupled heteromer is caused stress vulnerability.