The Dopamine Receptor D3 Regulates Lipopolysaccharide-Induced Depressive-Like Behavior in Mice

Abstract

BackgroundThe 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.MethodsIn 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.ResultsLPS 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.ConclusionsThese 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.

Homeostasis Imbalance of Microglia and Astrocytes Leads to Alteration in the Metabolites of the Kynurenine Pathway in LPS-Induced Depressive-Like Mice

“…A dose range of LPS at 0.32-2 mg/kg was selected based on a previous study [7]. The medium dose was set as 0.8 mg/kg in this study because it was used more frequently in a considerable number of studies [14]. The other two doses of LPS were 0.32 and 2 mg/kg, which were 2.5 folds lower and higher than 0.8 mg/kg, respectively.…”

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

“…Moreover, it is the leading cause of disability in modern society, and approximately one million people suffering from depression commit suicide every year [ 9 ]. It is widely recognized now that depression is closely linked with inflammation, and disrupted serotonergic systems throughout the human body, including the gut [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. In fact, in a state of inflammation, not only high levels of proinflammatory cytokines are produced but also altered levels of neurotransmitters, such as serotonin, a derivative of tryptophan metabolism, are detected in the gut [ 17 , 18 , 19 ].…”

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

“…Moreover, it is the leading cause of disability in modern society, and approximately 1 million people suffering from depression commit suicide every year [9]. It is widely recognized now that depression is closely linked with inflammation, and disrupted serotonergic systems throughout the human body, including the gut [10][11][12][13][14][15][16]. In fact, in a state of inflammation, not only high levels of pro-inflammatory cytokines are produced but also altered levels of neurotransmitters, such as serotonin, a derivative of tryptophan metabolism, are detected in the gut [17][18][19].…”