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Elucidation of the Central Serotonin Metabolism Pathway in Rhesus Macaques (Macaca mulatta) with Self-injurious Behavior
Author(s) -
Rachael L. Cohen,
Julia L. Drewes,
Suzanne E. Queen,
Zachary T. Freeman,
Kelly Metcalf Pate,
Robert J. Adams,
David R. Graham,
Eric K. Hutchinson
Publication year - 2021
Publication title -
comparative medicine
Language(s) - English
Resource type - Journals
eISSN - 2769-819X
pISSN - 1532-0820
DOI - 10.30802/aalas-cm-21-000020
Subject(s) - serotonin , kynurenine pathway , kynurenine , tryptophan , endocrinology , medicine , tryptophan hydroxylase , biology , reuptake , central nervous system , neurotransmitter , serotonergic , receptor , biochemistry , amino acid
Macaques with self-injurious behavior (SIB) have been used as a model of human SIB and have previously been shown to respond to treatments targeting enhancement of central serotonin signaling, whether by supplementation with tryptophan, or by inhibiting synaptic reuptake. Decreased serotonin signaling in the brain has also been implicated in many human psychopathologies including major depression disorder. A disturbance in tryptophan metabolism that moves away from the production of serotonin and toward the production of kynurenine has been proposed as a major etiological factor of depression. We hypothesized that in macaques with SIB, central tryptophan metabolism would be shifted toward kynurenine production, leading to lower central serotonin (5-hydroxytryptamine). We analyzed tryptophan metabolites in the cerebral spinal fluid (CSF) of macaques with and without SIB to determine whether and where tryptophan metabolism is altered in affected animals as compared with behaviorally normal controls. We found that macaques with SIB had lower CSF concentrations of serotonin than did behaviorally normal macaques, and that these deficits were inversely correlated with the severity of abnormal behavior. However, our results suggest that this decrease is not due to shifting of the tryptophan metabolic pathway toward kynurenine, as concentrations of kynurenine were also low. Concentrations of IL6 were elevated, suggesting central inflammation. Determining the mechanism by which serotonin function is altered in self-injurious macaques could shed light on novel therapies for SIB and other disorders of serotonin signaling.

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