Inflammatory status affects healthy brain function and also low-grade inflammation putatively contributes to the pathophysiology of Major Depressive Disorder (MDD). This psychoneuro-immunological interplay is complex, bidirectional, and not fully understood. Also, it is not clear to what extent depressive states induce inflammation and/or if increased inflammation leads to depressive symptoms by affecting brain biology including serotonin signaling. The serotonin 4 receptor (5-HT4R) is an interesting new antidepressant target; direct stimulation has antidepressant-like, and pro-cognitive effects, and may also index serotonin tone at least in the adult healthy brain. Here, we investigate whether a peripheral marker of low-grade inflammation (hsCRP) is associated with 5-HT4R brain binding in both a healthy and in an unmedicated MDD group. 5-HT4R PET imaging data and hsCRP measures from 112 healthy and 79 unmedicated MDD individuals were available from the Cimbi database. We evaluated the associations between hsCRP level and 5-HT4R binding in three regions of interest (neocortex, hippocampus, and neostriatum) using multiple linear regression models adjusted for relevant covariates. We did not observe a statistically significant association between hsCRP and 5-HT4R binding. This applied to both the healthy and the MDD group. Our findings do not support a coupling between low-grade inflammation and brain 5-HT4R availability, which suggests that the serotonergic system is not sensitive to low-grade inflammation captured by hsCRP, neither in healthy nor in depressed states. Future studies are needed to test if the brain serotonin system is coupled to other inflammatory markers, for instance in conditions with high-grade and/or prolonged immunoactivation.

Low-grade inflammation and serotonin 4 receptor binding in the healthy and the depressed brain