Dopamine D_2L Receptor Deficiency Causes Stress Vulnerability through 5-HT_1A Receptor Dysfunction in Serotonergic Neurons

Abstract

Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D 2 receptor (D 2 R), D 2L R, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT 1A R) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety-and depressive-like behaviors in D 2L R knockout (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT 1A R agonist, failed to alleviate the stress-induced behaviors in D 2L R-KO mice. In forced swim-stressed D 2L 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, D 2L R formed a heteromer with 5-HT 1A R in serotonergic neurons, thereby suppressing 5-HT 1A Ractivated G-protein-activated inwardly rectifying potassium conductance in D 2L R-KO serotonergic neurons. Finally, D 2L R overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D 2L R-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D 2L R/5-HT 1A heteromer causes stress vulnerability.

Sex-Specific Role for Dopamine Receptor D2 in Dorsal Raphe Serotonergic Neuron Modulation of Defensive Acoustic Startle and Dominance Behavior

“…Interestingly, a subset of Drd2 Pet1-CKO males (four out of 26) did display increased levels of aggressive behaviors as compared with other Drd2 Pet1-CKO mice and controls, suggesting there may be other influencing variables, yet unknown. This is plausible given that mice deficient for the long isoform of DRD2 (D 2L R) are reported to show anxiety-like and depressive-like behaviors only following a stress-exposure paradigm ( Shioda et al, 2019 ). Moreover, these stress-induced affective phenotypes in D 2L R knock-out mice were abrogated by driving D 2L R expression in DR Pet1+ serotonergic neurons ( Shioda et al, 2019 ).…”

“…This is plausible given that mice deficient for the long isoform of DRD2 (D 2L R) are reported to show anxiety-like and depressive-like behaviors only following a stress-exposure paradigm ( Shioda et al, 2019 ). Moreover, these stress-induced affective phenotypes in D 2L R knock-out mice were abrogated by driving D 2L R expression in DR Pet1+ serotonergic neurons ( Shioda et al, 2019 ). Together these findings suggest that the behavioral role of Drd2 expression in Drd2-Pet1 neurons may be influenced by environmental factors.…”

Aconitine disrupts serotonin neurotransmission via 5‐hydroxytryptamine receptor in zebrafish embryo

“…In our study, AC and 8‐OH‐DPAT both induced coiling behavior in zebrafish embryos (Figure 3), letting us to hypothesize that AC toxicity is mediated through 5‐HT1A receptor. The 5‐HT receptor agonist 8‐OH‐DPAT promotes 5‐HT efflux (Shioda et al, 2019), and selectively increases 5‐HT expression and turnover rate (Tran et al, 2018). The 5‐HT1A receptor antagonist WAY100635 blocks the 5‐HT1A receptor and down‐regulates 5‐HT1A receptor‐mediated extracellular‐regulated protein kinases (ERK) signaling pathway in the hypothalamus (Tran et al, 2018).…”

“…In our study, AC and 8-OH-DPAT both induced coiling behavior in zebrafish embryos (Figure 3), letting us to hypothesize that AC toxicity is mediated through 5-HT1A receptor. The 5-HT receptor agonist 8-OH-DPAT promotes 5-HT efflux (Shioda et al, 2019), and selectively increases 5-HT expression and turnover rate (Tran et al, 2018).…”

Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders

“…Evidence for the existence of D2 L R-5-HT1AR heterocomplexes has been gathered by both Lukasiewicz et al 2016 [ 148 ] and Shioda et al 2019 [ 149 ] in cellular models and in the dorsal raphe nucleus [ 149 ]. In addition, the presence of this heteroreceptor complex within the hippocampus and the coexistence of D2R and 5-HT1AR in cells of this area was immunohistochemically validated.…”