Department of Immunology and Pathogenic Biology, College of Basic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Department of Laboratory Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Int J Neuropsychopharmacol. 2018 May 1;21(5):448-460. doi: 10.1093/ijnp/pyy005.
The altered expression and function of dopamine receptor D3 (D3R) in patients and animal models have been correlated with depression disease severity. However, the morphological alterations and biological effects of D3R in the brain after inflammation-induced depressive-like behavior remain elusive.
In the present study, we ascertained the changes of D3R expression in the brain regions after depressive-like behavior induced by peripheral administration of lipopolysaccharide (LPS). Protein levels of proinflammatory cytokines, brain-derived neurotrophic factor (BDNF), and extracellular signal-regulated kinase (ERK1/2)-cAMP-response element-binding protein (CREB) signaling pathway after activation or inhibition of D3R in the brain of depressive mice were also investigated.
LPS caused a significant reduction of D3R in the ventral tegmental area (VTA), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), which are areas related to the mesolimbic dopaminergic system. Pretreatment with pramipexole (PPX), a preferential D3R agonist, showed antidepressant effects on LPS-induced depression-like behavior through preventing changes in LPS-induced proinflammatory cytokines (tumour necrosis factor-α, interleukin-1β, and interleukin-6), BDNF, and ERK1/2-CREB signaling pathway in the VTA and NAc. In opposition, treatment with a D3R selective antagonist NGB 2904 alone made mice susceptible to depression-like effects and caused changes in accordance with the LPS-induced alterations in proinflammatory cytokines, BDNF, and the ERK1/2-CREB signaling pathway in the mPFC and NAc.
These findings provide a relevant mechanism for D3R in LPS-induced depressive-like behavior via its mediation of proinflammatory cytokines and potential cross-effects between BDNF and the ERK1/2-CREB signaling pathway.
多巴胺受体 D3（D3R）在患者和动物模型中的表达和功能改变与抑郁症的严重程度有关。然而，在炎症引起的抑郁样行为后，D3R 在大脑中的形态改变和生物学效应仍然难以捉摸。
在本研究中，我们确定了外周给予脂多糖（LPS）诱导抑郁样行为后大脑中 D3R 表达的变化。还研究了 D3R 在抑郁小鼠大脑中被激活或抑制后，促炎细胞因子、脑源性神经营养因子（BDNF）和细胞外信号调节激酶（ERK1/2）-cAMP 反应元件结合蛋白（CREB）信号通路的蛋白水平。
LPS 导致腹侧被盖区（VTA）、内侧前额叶皮层（mPFC）和伏隔核（NAc）中 D3R 的显著减少，这些区域与中脑边缘多巴胺能系统有关。预先给予普拉克索（PPX），一种优先 D3R 激动剂，通过防止 LPS 诱导的促炎细胞因子（肿瘤坏死因子-α、白细胞介素-1β 和白细胞介素-6）、BDNF 和 VTA 和 NAc 中的 ERK1/2-CREB 信号通路的变化，对 LPS 诱导的抑郁样行为表现出抗抑郁作用。相反，单独使用 D3R 选择性拮抗剂 NGB 2904 使小鼠易患抑郁样效应，并导致与 LPS 诱导的促炎细胞因子、BDNF 和 mPFC 和 NAc 中的 ERK1/2-CREB 信号通路改变相一致的变化。
这些发现为 D3R 通过其对促炎细胞因子的介导以及 BDNF 和 ERK1/2-CREB 信号通路之间的潜在交叉效应在 LPS 诱导的抑郁样行为中的作用提供了一个相关的机制。
