Serotonin catabolism in the central and enteric nervous systems of rats upon induction of serotonin syndrome

Abstract

Serotonin, a well-known neurotransmitter in mammals, has been linked to a number of neurological and gastrointestinal disorders. One of these disorders, serotonin syndrome, is a potentially deadly condition caused by increased levels of serotonin in the extracellular space. Information on the neurochemical effects of serotonin syndrome on serotonin catabolism is lacking, particularly in relation to the enteric system of the gastrointestinal tract. Here the catabolism of serotonin is monitored in rats with pharmacologically induced serotonin syndrome, with the catabolites characterized using a specialized capillary electrophoresis system with laser-induced native fluorescence detection. Animals induced with serotonin syndrome demonstrate striking increases in the levels of serotonin and its metabolites. In the brain, levels of serotonin increased 2-to 3-fold in animals induced with serotonin syndrome. A major serotonin metabolite, 5-hydroxyindole acetic acid, increased 10-to 100-fold in experimental animals. Similar results were observed in the gastrointestinal tissues; in the small intestines, serotonin levels increased 4-to 5-fold. Concentrations of 5-hydroxyindole acetic acid increased 32-to 100-fold in the intestinal tissues of experimental animals. Serotonin sulfate showed surprisingly large increases, marking what may be the first time the compound has been reported in rat intestinal tissues. Keywords: capillary electrophoresis system with laserinduced native fluorescence detection, enteric nervous system, serotonin, serotonin metabolism, serotonin sulfate, serotonin syndrome. Serotonin (5-HT) is well known as a neurotransmitter in the CNS of mammals where it plays an important role in learning and memory (Martin et al. 1997;Buhot et al. 2000) and in various stages of development (Gaspar et al. 2003). Imbalances in levels of 5-HT have been observed in a number of neurological disorders including: Parkinson, Huntington, Alzheimer, Alzheimer-like dementia, anxiety, and depression (Osborne and Hamon 1988). Although the majority of research aimed at understanding 5-HT function, release, uptake, and metabolism has focused on the CNS, an estimated 95% of the 5-HT in the human body is located in the PNS of the gastrointestinal tract, the enteric nervous system (ENS) (Kim and Camilleri 2000). 5-HT fulfills all criteria necessary for classification as a neurotransmitter in the ENS (Gershon 2004) and has been linked to a number of gastrointestinal disorders including irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, and gastric ulcer formation (Orlicz-Szczesna et al. 1989;Dhasmana et al. 1993). Thus, it is important to consider 5-HT metabolism in both the ENS and CNS. Understanding the catabolic pathways, the enzymes involved and the products of these conversions is particularly important because catabolism is vital to the regulation of 5-HT levels. Elucidating 5-HT catabolic pathways (Fig. 1) may provide novel approaches for the regulation of this compound and thus, improved targets for...

Lamp‐based wavelength‐resolved fluorescence detection for protein capillary electrophoresis: Setup and detector performance

“…The high irradiance and directionality of lasers are advantageous for focussing light into the small detection volume inside the capillary. CE-WRFlu has primarily been used for the analysis of native-fluorescent or fluorescently-labelled low-molecular-weight compounds such as dyes [6,7], metabolites [8][9][10], neurotransmitters [11][12][13][14][15][16][17], polyaromatic compounds [18,19], collagen cross linkers [20] and isoflavanoids [21]. Timperman et al [22,23] have analysed tyrosine and Trp-containing peptides, and Fultz et al [24] have measured dye-labelled proteins with LIF-based CE-WRFlu.…”

Application of 5-HT-SO4 in Biomarker Research

“…As the liver processes the portal circulation, enzymes rapidly degrade the It should be noted that 5-HT taken up by platelets is protected from degradation in the liver and enters the general blood circulation [18]. Coincidentally, the only sites of 5-HT sulphation identiied in humans are the CNS and enteric nervous systems [6,19] while enteric nervous system 5-HT-SO 4 was found only after induction of serotonin syndrome [19]. Some isoforms of SULT have been shown to have sulphate serotonin [20].…”

The serotonin-O-sulfate as a potential plasma surrogate biomarker

“…Importantly, 5-HT absorbed by thrombocytes is secured from biotransformation by the liver enzymes and enters the general blood circulation [21] . In a same time the only sites of serotonin sulfation identified so far in humans are the central and enteric nervous systems [22,13] . An enteric nervous system 5-HT-SO4 was detected only after induction of serotonin syndrome [22] .…”

“…In a same time the only sites of serotonin sulfation identified so far in humans are the central and enteric nervous systems [22,13] . An enteric nervous system 5-HT-SO4 was detected only after induction of serotonin syndrome [22] .…”