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

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          Abstract

          Background

          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.

          Methods

          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.

          Results

          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.

          Conclusions

          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.

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          Most cited references67

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          A molecular and cellular theory of depression.

          R S Duman, G Heninger, E J Nestler (1997)
          Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.
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            The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression.

            Yong-Ku Kim, Kyoung-Sae Na, Aye-Mu Myint … (2016)
            Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation, which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus-pituitary-adrenal (HPA) axis have close interactions with pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation.
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              Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.

              Yogesh Dwivedi, Hooriyah S. Rizavi, Robert Conley … (2003)
              Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions. These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase-polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas. Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain. Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.
              Article 0 comments Cited 209 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Neuropsychopharmacol
                Journal ID (iso-abbrev): Int. J. Neuropsychopharmacol
                Journal ID (publisher-id): ijnp
                Title: International Journal of Neuropsychopharmacology
                Publisher: Oxford University Press (US )
                ISSN (Print): 1461-1457
                ISSN (Electronic): 1469-5111
                Publication date Collection: May 2018
                Publication date (Electronic): 30 January 2018
                Publication date PMC-release: 30 January 2018
                Volume: 21
                Issue: 5
                Pages: 448-460
                Affiliations
                [1 ]Department of Immunology and Pathogenic Biology, College of Basic Medicine, Xi’an Jiaotong University Health Science Center, Xi’an, China
                [2 ]Department of Laboratory Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University Health Science Center, Xi’an, China
                [3 ]Forensic Medicine College of Xi’an Jiaotong University, Key Laboratory of the Health Ministry for Forensic Medicine, Xi’an, China
                Author notes
                Correspondence: Yanjiong Chen, PhD, Department of Immunology and Pathogenic Biology, College of Basic Medicine, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China ( chenyanjiong@ 123456126.com )
                Article
                Publisher ID: pyy005
                DOI: 10.1093/ijnp/pyy005
                PMC ID: 5932470
                PubMed ID: 29390063
                SO-VID: 6de35818-ea37-4137-bc97-de2b56429ef0
                Copyright © © The Author(s) 2018. Published by Oxford University Press on behalf of CINP.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 14 September 2017
                Date revision received : 10 December 2017
                Date accepted : 26 January 2018
                Page count
                Pages: 13
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81273196
                Award ID: 81430048
                Categories
                Subject: Regular Research Articles

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: dopamine receptor d3,inflammation,bdnf,erk1/2-creb signaling pathway
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: dopamine receptor d3, inflammation, bdnf, erk1/2-creb signaling pathway

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