Targeting dopamine receptor D3 signalling in inflammation

During last 15 years dopamine has emerged as a major regulator of inflammation. All five dopamine receptors (DRs, DRD1-DRD5) have been found to be expressed in immune cells where they exert a complex regulation of immunity [1]. Of note, DRs have been found not only in cells of the adaptive immune system, but also in cells belonging to the innate immunity, even including glial cells. The outcome of the dopamine effect in the immune response depends in many factors, including differential expression of DRs in the immune cells present in the inflamed tissue, the local levels of dopamine and the signalling coupled to and the affinity of the different DRs involved. An increasing number of studies analysing human cells in vitro or using in vivo approaches in animal models have been unravelling and deciphering the complexity of dopaminergic regulation of immunity. Integrating the knowledge acquired by these studies, the evidence have indicated that stimulation of lowaffinity DRs, for instance DRD1 and DRD2, are coupled to anti-inflammatory mechanisms, thereby dampening inflammation [2, 3]. Conversely, signalling triggered by high-affinity DRs, including DRD3 and DRD5, have been found consistently to promote inflammation [4, 5]. It is noteworthy that tissues containing high-levels of dopamine in steady-state, such as the nigrostriatal pathway or the gut mucosa, undergo a strong decrease of dopamine levels during inflammation [1]. This fact involves a switch in the stimulation of DRs: low-affinity DRs, which display anti-inflammatory properties and are stimulated by high dopamine levels under homeostasis, are not longer stimulated during inflammatory processes. Otherwise, signalling coupled to high-affinity DRs, which seems to be dampened by low-affinity DRs stimulation under homeostasis, becomes dominant when dopamine levels are reduced during inflammation. This idea highlight the relevance of high-affinity DRs favouring the development and progression of inflammatory disorders and makes these receptors key therapeutic targets. Accordingly, DRD3, which display the highest affinity by dopamine, has been strongly involved in favouring inflammation in several experimental systems. In this regard, genetic and pharmacological evidence has indicated that DRD3-signalling constitutes a potent regulator of CD4+ T-cell-mediated responses, including those implicated in Parkinson’s disease [6] and inflammatory colitis [4], two pathologies that involve