Original ResearchFull Report: Basic and Translational—Alimentary TractEffects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression
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Animals
Male and female TPH2-R439H mice (c57BL6/J–129S6/SvEvTac background) were bred at Duke University (Durham, NC) and shipped to Columbia University Medical Center (New York, NY) or bred at CUMC.34 Experiments were conducted with homozygous wild-type (WT) and TPH2-R439H littermates. 5-HTP immediate release (IR) was administered intraperitoneally in a dose-response fashion, from 1 to 100 mg/kg. The 5-HTP SR (≅1 g/kg/day, 6.7 mg 5-HTP/g chow; created by mixing the 5-HTP in finely crushed chow with a
The TPH2-R439H Polymorphism Results in Decreased Levels of Enteric Neuronal Serotonin and Impedes Enteric Nervous System Development
TPH2 is required for 5-HT production in enteric neurons.13 Immunocytochemistry and calcium (Ca2+) channel imaging were thus used to assess the 5-HT content of the ENS and enteric neurons, respectively, in TPH2-R439H mice and WT littermates. Significantly fewer 5-HT–immunoreactive nerve cell bodies were detected in TPH2-R439H mice than in WT controls (Figure 1 and Supplementary Table 1). This deficit was manifest both in total numbers of serotonergic neurons and as the proportion of total
Discussion
GI problems and mood disorders are often comorbid. Few underlying links, however, are known. Mice with a polymorphism that alters neuronal 5-HT production, TPH2-R439H, were previously found to manifest depression- and anxiety-like behaviors, similar to individuals with an analogous human single-nucleotide polymorphism, TPH2-R441H.21 CNS 5-HT production is known to be deficient in TPH2-R439H mice, and TPH2 is responsible for 5-HT biosynthesis in both the ENS and the CNS. We therefore tested the
Acknowledgements
Author contributions: Kara G. Margolis, Narek Israelyan, and Andrew Del Colle designed and conducted the studies, analyzed data, and wrote the manuscript. Andrew Del Colle, Yeji Park, Albert Xing, Ruth Ann Luna, Dane D. Jensen, Moneek Madra, Virginia Saurman, Ray Rahim, Rocco Latorre, Kimberly Law, William Carson, and Nigel W. Bunnett conducted experiments and acquired data. Mark G. Caron and Jacob P.R. Jacobsen created and provided mice, conducted experiments, and analyzed data. All coauthors
References (42)
- et al.
Comparison of comorbid depression between irritable bowel syndrome and inflammatory bowel disease: a meta-analysis of comparative studies
J Affect Disord
(2018) - et al.
The serotonin signaling system: from basic understanding to drug development for functional GI disorders
Gastroenterology
(2007) - et al.
Adjunctive 5-hydroxytryptophan slow-release for treatment-resistant depression: clinical and preclinical rationale
Trends Pharmacol Sci
(2016) - et al.
Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response
Prog Neuropsychopharmacol Biol Psychiatry
(2009) - et al.
Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression
Neuron
(2005) - et al.
Altered fecal microbiota composition in patients with major depressive disorder
Brain Behav Immun
(2015) - et al.
Prevotella and Klebsiella proportions in fecal microbial communities are potential characteristic parameters for patients with major depressive disorder
J Affect Disord
(2017) - et al.
Control of brain development, function, and behavior by the microbiome
Cell Host Microbe
(2015) - et al.
l-5-hydroxytryptophan augments the neuroendocrine response to a SSRI
Psychoneuroendocrinology
(2006) - et al.
Hu antigen specificities of ANNA-I autoantibodies in paraneoplastic neurological disease
J Autoimmun
(1999)
Physiological responses of guinea-pig myenteric neurons secondary to the release of endogenous serotonin by tryptamine
Neuroscience
Evidence that myoelectric complexes in the isolated mouse colon may not be of myogenic origin
Neurosci Lett
Prevalence of depression among adults aged 20 and over: United States, 2013–2016
NCHS Data Brief
Epidemiology and burden of chronic constipation
Can J Gastroenterol
Psychological disorders in patients with chronic constipation
Gastroenterol Hepatol Bed Bench
Into the bowels of depression: unravelling medical symptoms associated with depression by applying machine-learning techniques to a community based population sample
PLoS One
Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis
Eur Arch Psychiatry Clin Neurosci
The increased level of depression and anxiety in irritable bowel syndrome patients compared with healthy controls: systematic review and meta-analysis
J Neurogastroenterol Motil
The bowel and beyond: the enteric nervous system in neurological disorders
Nat Rev Gastroenterol Hepatol
5-Hydroxytryptamine (serotonin) in the gastrointestinal tract
Curr Opin Endocrinol Diabetes Obes
Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons
J Neurosci
Cited by (0)
Conflicts of interest These authors disclose the following: Jacob P.R. Jacobsen and Marc G. Caron are inventors on US patents pertaining to the adjunct 5-HTP SR method of treatment and hold equity in Evecxia Inc, a company founded to develop a 5-HTP slow-release drug for the management of serotonin-related disorders. The remaining authors disclose no conflicts.
Funding This work was supported by National Institutes of Health grants DK093786 (Kara G. Margolis), NS15547 (Kara G. Margolis), MH79201 (Mark G. Caron), T35AG044303 (Narek Israelyan), NS102722 (Nigel W. Bunnett), DE026806 (Nigel W. Bunnett), and DK118971 (Nigel W. Bunnett); US Department of Defense grants PR160365 (Kara G. Margolis) and PR170507 (Nigel W. Bunnett); American Gastroenterological Association Student Research Fellowship Award (Narek Israelyan); the Lundbeck Foundation (Jacob P.R. Jacobsen); and gifts from the Phyllis and Ivan Seidenberg Family Fund for Children’s Digestive Health (Kara G. Margolis) and The Lennon Family (Mark G. Caron).