Also see:
Antidepressant use in pregnancy linked to autism risk in boys: Study
Hypothyroidism and Serotonin
Estrogen Increases Serotonin
Tryptophan Metabolism: Effects of Progesterone, Estrogen, and PUFA
Omega -3 “Deficiency” Decreases Serotonin Producing Enzyme
Serotonin Reuptake ENHANCER as Anti-Depressant
Therapeutic Effects of Bromocriptine
Acute Appendicitis and Serotonin
Enzyme to Know: Tryptophan Hydroxylase
Serotonin and Melatonin Lower Progesterone
Role of Serotonin in Preeclampsia
PUFA, Development, and Allergy Incidence
Maternal exposure to anti-depressant SSRIs linked to autism in children
“In autism, repetitive motions are a common symptom, and serotonin is high in the blood serum and platelets of autistic children and their relatives.” -Ray Peat, PhD
Med Hypotheses. 2010 May;74(5):880-3. doi: 10.1016/j.mehy.2009.11.015. Epub 2009 Dec 16.
Serotonin, pregnancy and increased autism prevalence: is there a link?
Hadjikhani N.
The prevalence of autism, a neurodevelopmental condition resulting from genetic and environmental causes, has increased dramatically during the last decade. Among the potential environmental factors, hyperserotonemia during pregnancy and its effect on brain development could be playing a role in this prevalence raise. In the rodent model developed by Whitaker-Azmitia and colleagues, hyperserotonemia during fetal development results in a dysfunction of the hypothalamo-pituitary axis, affecting the amygdala as well as pro-social hormone oxytocin regulation. Dysfunction of the amygdala and abnormal oxytocin levels may underlie many clinical features of ASD. Selective serotonin reuptake inhibitors (SSRI) are the most widely used class of antidepressants drugs, and they are not contraindicated during pregnancy. In this paper, we hypothesize that increased serotonemia during pregnancy, including due to SSRI intake, could be one of the causes of the raising prevalence in autism. If our hypothesis is confirmed, it will not only shed light on one of the possible reason for autism prevalence, but also offer new preventive and treatment options.
J Neuropsychiatry Clin Neurosci. 1990 Summer;2(3):268-74.
Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence.
Cook EH Jr, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX.
Whole-blood serotonin (5-HT) and plasma norepinephrine (NE) were studied in 16 autistic children, 21 siblings of autistic children, and 53 parents of autistic children. Both plasma NE and whole-blood 5-HT were negatively correlated with vocabulary performance. Whole-blood 5-HT and plasma NE did not differ between autistic children with or without histories of self-injurious behavior or decreased pain sensitivity. Eighteen subjects were hyperserotonemic (whole-blood 5-HT greater than 270 ng/ml). For these subjects, plasma NE was significantly higher than for subjects without hyperserotonemia. Seven of 10 families with one hyperserotonemic member had two or more hyperserotonemic members. Observations of familiarity of whole-blood 5-HT suggest that larger-scale and more focused study of whole-blood 5-HT as a possible genetic marker may be productive.
J Autism Dev Disord. 1990 Dec;20(4):499-511.
Relationships of whole blood serotonin and plasma norepinephrine within families.
Leventhal BL, Cook EH Jr, Morford M, Ravitz A, Freedman DX.
Whole blood serotonin (5HT) and plasma norepinephrine (NE) levels were determined in 47 families of autistic probands to study relationships within families of these measures. Whole blood 5HT, but not plasma NE, was significantly positively correlated between autistic children and their mothers, fathers, and siblings. Twenty-three of the 47 families studied had at least 1 hyperserotonemic member. Of these 23 families, 10 (43.5%) had 2 or more hyperserotonemic members; 5 families were identified in which each family member studied had hyperserotonemia (whole blood 5HT greater than 270 ng/ml). If the autistic child of a family was hyperserotonemic, the first-degree relatives were 2.4 times more likely to be hypersertonemic than if the autistic child was not hyperserotonemic. Mean whole blood 5HT levels were higher in autistic subjects than their parents or siblings. Siblings were found to have lower plasma NE than autistic probands. This study replicates a previous study showing familial relationships of hyperserotonemia within families with autistic children.
Arch Gen Psychiatry. 1977 May;34(5):521-31.
Hyperserotonemia and amine metabolites in autistic and retarded children.
Hanley HG, Stahl SM, Freedman DX.
Mean whole blood serotonin (5-HT) levels were elevated in groups of autistic and severely retarded children. Eight of 27 (30%) individual autistic children, 13 of 25 (52%) severely retarded children, two of 23 (9%) mildly retarded children, and none of the control children had statistically significant blood 5-HT levels elevations (hyperserotonemia). Hyperserotonemic autistic children excreted more urinary 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptamine, and vanillylmandelic acid than did mildly retarded children with normal blood 5-HT levels. Rates of depletion and repletion of blood 5-HT levels in these two groups following reserpine therapy were identical. Oral tryptophan administration doubled urinary 5-HIAA excretion in both groups and raised urinary 5-HT levels in hyperserotonemic autistic children, but lowered urinary 5-HT in mildly retarded, normal blood 5-HT children. No clear mechanism for hyperserotonemia was found; the rationale for further investigations is discussed.
Int J Dev Neurosci. 2005 Feb;23(1):75-83.
Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?
Whitaker-Azmitia PM.
The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so-called hyperserotonemia of autism) may lead to some of the behavioral and cellular changes also observed in the disorder. At early stages of development, when the blood-brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5-methoxytryptamine (5-MT). In work using 5-MT to mimic hyperserotonemia, Sprague-Dawley rats are treated from gestational day 12 until postnatal 20. In published reports, these animals have been found to have a significant loss of serotonin terminals, decreased metabolic activity in cortex, changes in columnar development in cortex, changes in serotonin receptors, and “autistic-like” behaviors. In preliminary cellular findings given in this review, the animals have also been found to have cellular changes in two relevant brain regions: 1. Central nucleus of the amygdala, a brain region involved in fear-responding, where an increase in calcitonin gene related peptide (CGRP) was found 2. Paraventricular nucleus of the hypothalamus, a brain region involved in social memory and bonding, where a decrease in oxytocin was found. Both of these cellular changes could result from loss of serotonin innervation, possibly due to loss of terminal outgrowth from the same cells of the raphe nuclei. Thus, increased serotonergic activity during development could damage neurocircuitry involved in emotional responding to social stressors and may have relevance to the symptoms of autism.
Physiol Behav. 2002 Mar;75(3):403-10.
Behavioral and magnetic resonance spectroscopic studies in the rat hyperserotonemic model of autism.
Kahne D, Tudorica A, Borella A, Shapiro L, Johnstone F, Huang W, Whitaker-Azmitia PM.
Autism is classified as a pervasive developmental disorder, with several cardinal features including sensory disturbances, obsessive-compulsive-like behavior, lack of bonding to caregivers and motor disturbances. To date, there is a lack of an animal model of the disease. The current work is aimed at producing such a model by treating developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational age 12 days to postnatal day 20), thus mimicking one of the hallmark neurochemical features of the illness-increases in the neurotransmitter, serotonin. Animals were then tested in behavioral paradigms that may resemble the human illness. Treated rat pups were found to be overreactive to auditory or tactile sensory stimuli, to display changes in the negative geotaxic test of motor development, to show lack of separation-induced vocalizations when their dam was removed and to show decreased alternation in the spontaneous alternation task. As well, the animals showed metabolic abnormalities in the brain using in vivo proton magnetic resonance spectroscopy, which are consistent with those observed in autistic children. In summary, the model we are proposing shows some of the behavioral and metabolic features of autism, as well as being produced through alteration of a neurochemical system known to be altered in autism.
The Journal of Neuroscience, 1 June 2016, 36(22): 6041-6049; doi: 10.1523/JNEUROSCI.2534-15.2016
Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain
Nick Goeden1, Juan Velasquez, Kathryn A. Arnold, Yen Chan, Brett T. Lund, George M. Anderson6, and Alexandre Bonnin
Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternal L-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment.
SIGNIFICANCE STATEMENT The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.
