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 (D2 R), D2L R, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1A R) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2L R knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1A R agonist, failed to alleviate the stress-induced behaviors in D2L R-KO mice. In forced swim-stressed D2L R-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, D2L R formed a heteromer with 5-HT1A R in serotonergic neurons, thereby suppressing 5-HT1A R-activated G-protein-activated inwardly rectifying potassium conductance in D2L R-KO serotonergic neurons. Finally, D2L R overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2L R-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2L R/5-HT1A heteromer causes stress vulnerability. SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2L R, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1A R in serotonergic neurons. The D2L R/5-HT1A R inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.