Abstract
BackgroundPrefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in patients with bipolar disorder in plasma samples, imaging studies and postmortem tissue and is an indicator for an inflammatory state. We could previously show that lentiviral overexpression of D1R in the medial prefrontal cortex (mPFC) of male adult rats and its termination induces bipolar disorder-like behavior. The purpose of this study was to investigate anxiety and the role of the immune system, specifically IL-6 positive neurons in this animal model. Due to its high density of inflammatory mediator receptors and therewith sensibility to immune activation, the hippocampus was investigated.MethodsExpression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible lentiviral vector. Animals over-expressing the gene (mania-like state), after termination of the expression (depressive-like) and their respective control groups were investigated. Anxiety behavior was studied in the elevated plus maze and marble burying test. Furthermore, IL-6-positive cells were counted within several subregions of the hippocampus.ResultsD1R manipulation in the mPFC had only mild effects on anxiety behavior in the elevated plus maze. However, subjects after termination buried more marbles compared to D1R over-expressing animals and their respective control animals indicating elevated anxiety behavior. In addition, animals in the depressive-like state showed higher numbers of IL-6 positive cells reflecting an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus. Consistently, inflammatory state in the whole hippocampus and anxiety behavior correlated positively, indicating a connection between anxiety and inflammatory state of the hippocampus.ConclusionsBehavioral and neurobiological findings support the association of manipulation of the D1R in the mPFC on anxiety and inflammation in the hippocampus. In addition, by confirming changes in the inflammatory state, the proposed animal model for bipolar disorder has been further validated.
Highlights
Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder
Based on the importance of hippocampal inflammatory state as outlined above we investigated an aberrant activation of the immune system, via analyzing the number of IL-6-positive cells in the hippocampus
Our results demonstrate an increase of inflammatory activation in the hippocampus, in the CA3 and Dentate gyrus (DG) area, following D1R over-expression and its termination in glutamatergic neurons of the medial prefrontal cortex (mPFC)
Summary
Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Beyer et al Int J Bipolar Disord (2021) 9:9 intense during mood episodes, especially manic episodes, and less intense in depressive episodes (Lu et al 2019; Modabbernia et al 2013) These findings are supported by phasic differences in the peripheral levels of cytokines in BD patients (Ortiz-Domínguez et al 2007). Abnormalities of the immune system have been linked to symptom severity (Goldstein et al 2009), state of mood episodes (Brietzke et al 2009b; Ortiz-Domínguez et al 2007) and treatment effect (Benedetti et al 2017; Goldstein et al 2009) These findings are supported by the evidence, that adjunctive treatment with some anti-inflammatory agents is able to alleviate manic and improve depressive symptoms (Goldsmith et al 2016; Köhler et al 2014). Pro-inflammatory cytokines can be attenuated by lithium (Himmerich et al 2013; Patel and Frey 2015)
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