Dopamine D_2L receptor deficiency causes stress vulnerability through 5-HT_1A receptor dysfunction in serotonergic neurons

Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D₂ receptor (D₂R), D_2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT_1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D_2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT_1AR agonist, failed to alleviate the stress-induced behaviors in D_2LR-KO mice. In forced swim-stressed D_2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D_2LR formed a heteromer with 5-HT_1AR in serotonergic neurons, thereby suppressing 5-HT_1AR-activated G-protein-activated inwardly rectifying potassium conductance in D_2LR-KO serotonergic neurons. Finally, D_2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D_2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D_2LR/5-HT_1A heteromer causes stress vulnerability.