Date of Award
Open Access Dissertation
Depression is the leading cause of disability worldwide. Disorders of the brain, including depression, are notoriously difficult to treat because the basic pathology underlying behavioral outcomes remains undefined. Robust chemical biomarkers of these diseases have not been identified, nor are there reliable methods to measure brain chemicals. Depression is associated with chemical and inflammatory changes in the brain that are predicted to contribute to the pathology. By studying the serotonin and histamine systems we aim to better define the neurochemical basis of depression. Serotonin has long been hypothesized to play a role in depression since selective serotonin reuptake inhibitors (SSRIs) are the frontline treatment for depression. Histamine has a well-established role in peripheral inflammation and novel data from the Hashemi lab showing that histamine release inhibits serotonin signaling justifies the need to consider the two neurotransmitters in tandem. In this work, fast-scan cyclic voltammetry (FSCV)/fast-scan controlled adsorption voltammetry (FSCAV) were used to measure serotonin release/reuptake and ambient concentration in the hippocampus and simultaneously measure histamine and serotonin in the posterior hypothalamus of rodents (both male and female). I found that both serotonin and histamine signals are consistent across the sexes, however, pharmacological intervention does tease out some differences in the neurochemical systems. Next, I employed a SSRI resistant mouse model (SERT Met172) to study how commonly prescribed SSRIs interact with serotonin. Models of acute (peripheral injection of lipopolysaccharide) or chronic (chronic mild stress and high fat diet (45 kcal % fat)) neuroinflammation were applied to assess effects on serotonin and histamine. Biochemical (for inflammation) and behavioral (for depression) analysis were correlated with neurochemical measurements. The data suggested that inflammation corresponds to increased histamine release, thus increased serotonin inhibition. I also found that the capacity of SSRIs to increase extracellular serotonin by inhibiting serotonin transporters (SERTs) was reduced in both inflammation models. However, by inhibiting histamine synthesis, the ability of SSRIs to increase extracellular serotonin was restored. My results suggest that histamine plays a fundamental role in modulating serotonin during inflammation. This deeper insight into the neurochemical basis of depressive illness shines a spotlight on histamine as a novel therapeutic target. .
Hersey, M.(2020). The Role of Acute and Chronic Neuroinflammation in Depression: Uncovering the Relationship Between Histamine and Serotonin Transmission. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5679