Significant research efforts have focused on advancing our understanding of serotonin (5-HT) 2 function and its mechanism of release, uptake, and metabolism. The majority of this research has involved the central nervous system, where imbalances in 5-HT levels have been linked to various diseases, including Parkinson, Huntington, Alzheimer, Alzheimer-like dementia, anxiety, and depression (1), and its regulation depends on a multitude of 5-HT receptors and neurochemical pathways (2). Other 5-HT functions within the brain involve learning and memory (3, 4) and regulation of various stages of development (5). However, neither 5-HT nor its effects are limited to the central nervous system; 5-HT is found in most smooth muscles in the body and is responsible for the induction of the contractile responses of the gastrointestinal, pulmonary, and genito-urinary systems (6). Specifically, researchers estimate that 95% of the approximate 10 mg of 5-HT in the human body is produced in the enteric nervous system, which includes both the peripheral nervous system of the gastrointestinal tract, as well as the 5-HT-secreting enterochromaffin cells of the gut lining (7). In the enteric nervous system, 5-HT fulfills all criteria necessary for classification as a neurotransmitter (8). Imbalances in 5-HT levels within the enteric nervous system have been observed in association with various disorders, including irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, and gastric ulcer formation (6, 9). Our focus is to gain insight into the pathways by which 5-HT is catabolized and the compounds into which it is converted. Because of its high biological potency, tight regulation of 5-HT levels in specific nervous system regions is necessary, and 5-HT catabolism plays an important role in this regulation. Because 5-HT conversion into these other compounds affects the overall levels of 5-HT, formation of these conversion products can be a fundamental factor in 5-HT regulation.Scheme 1 represents the main 5-HT metabolic pathways and enzymes; however, these represent only a subset of the pathways of 5-HT metabolism, as other lower abundance serotonin metabolites, such as 5-HT sulfate, are known. In immune response pathways, compounds such as formyl 5-HT and 5-hydroxykynuremine (10) are additional serotonin metabolic products. Research performed in the 1950s to track the metabolism of radiolabeled tryptophan demonstrated a number of unknown 5-HT metabolites, proposed to result from additional branches of the monoamine oxidase (MAO) pathway (11). MAO exists in two forms, MAOa and MAOb (12); the former is the primary form of the enzyme responsible for the conversion of 5-HT, although, in the absence of MAOa, MAOb takes over the 5-HT conversion process. With a more in-depth understanding of this, and other potential tissue-specific 5-HT catabolic pathways, it may be possible to develop methods for controlling serotonergic levels in a tissue-specific manner.In this study, we identify unique 5-HT metabolites by analyzing 5-HTp...

A library of tripodal amine ligands with two oxime donor arms and a variable coordinating or noncoordinating third arm has been synthesized, including two chiral ligands based on l-phenylalanine. Their Ni(II) complexes have been synthesized and characterized by X-ray crystallography, UV-vis absorption, circular dichroism, and FTIR spectroscopy, mass spectrometry, and room-temperature magnetic susceptibility. At least one crystal structure is reported for all but one Ni/ligand combination. All show a six-coordinate pseudo-octahedral coordination geometry around the nickel center, with the bis(oxime)amine unit coordinating in a facial mode. Three distinct structure types are observed: (1) for tetradentate ligands, six-coordinate monomers are formed, with anions and/or solvent filling out the coordination sphere; (2) for tridentate ligands, six-coordinate monomers are formed with Ni(II)(NO(3))(2), with one monodentate and one bidentate nitrate filling the remaining coordination positions; (3) for tridentate ligands, six-coordinate, bis(mu-Cl) dimers are formed with Ni(II)Cl(2), with one terminal and two bridging chlorides filling the coordination sphere. The UV-vis absorption spectra of the complexes show that the value of 10 Dq varies according to the nature of the third arm of the ligand. The trend based on the third arm follows the order alkyl/aryl < amide < carboxylate < alcohol < pyridyl < oxime.

SUMMARY Serotonin (5-HT), an important molecule in metazoans, is involved in a range of biological processes including neurotransmission and neuromodulation. Both its creation and release are tightly regulated, as is its removal. Multiple neurochemical pathways are responsible for the catabolism of 5-HT and are phyla specific; therefore, by elucidating these catabolic pathways we glean greater understanding of the relationships and origins of various transmitter systems. Here, 5-HT catabolic pathways were studied in Strongylocentrotus purpuratus and Xenoturbella bocki, two organisms occupying distinct positions in deuterostomes. The 5-HTrelated compounds detected in these organisms were compared with those reported in other phyla. In S. purpuratus, 5-HT-related metabolites include N-acetyl serotonin, -glutamyl-serotonin and 5-hydroxyindole acetic acid; the quantity and type were found to vary based on the specific tissues analyzed. In addition to these compounds, varying levels of tryptamine were also seen. Upon addition of a 5-HT precursor and a monoamine oxidase inhibitor, 5-HT itself was detected. In similar experiments using X. bocki tissues, the 5-HT-related compounds found included 5-HT sulfate, -glutamyl-serotonin and 5-hydroxyindole acetic acid, as well as 5-HT and tryptamine. The sea urchin metabolizes 5-HT in a manner similar to both gastropod mollusks, as evidenced by the detection of -glutamyl-serotonin, and vertebrates, as indicated by the presence of 5-hydroxyindole acetic acid and N-acetyl serotonin. In contrast, 5-HT metabolism in X. bocki appears more similar to common protostome 5-HT catabolic pathways.

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...

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