Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice

Sackler Institute for Developmental Psychobiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Science (Impact Factor: 33.61). 10/2004; 306(5697):879-81. DOI: 10.1126/science.1101678
Source: PubMed


Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

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    • "Anatomical MRI studies showed that individuals who had the " s " allele had decreased gray matter volumes in the pACC and the amygdala (Pezawas et al., 2005), regions intimately involved in emotional response (Pezawas et al., 2005) and mood. These alterations in brain function and morphology could be due to the morphological consequences of the altered serotonin signaling in fetus during brain development (Ansorge et al., 2004;Esaki et al., 2005;Homberg et al., 2010). We therefore expected these morphological consequences to be present in individuals who were at a greater risk for developing depression, regardless of their lifetime history for depression. "
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    ABSTRACT: Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The “s” allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.
    Full-text · Article · Jan 2016 · Psychiatry Research: Neuroimaging
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    • "The 5-HTT KO mouse has anxiety-like [65] and lessconsistently depression-like behaviors [66,67], while rodents treated with fluoxetine during adulthood show behavioral sensitization to amphetamine and ethanol [68] [69]. It is possible that reduced brain ARA metabolism on neuroimaging and downregulation of the CYP4A pathway producing 20- HETE contributes to reported depressive-like [16–19,70–72] and anxiety-like behaviors [16] [20] in adult mice given fluoxetine postnatally. These long-term quasi-permanent effects of transient postnatal fluoxetine suggest epigenetic or other neuroplastic mechanisms, since 5-HT and its metabolites are absent from brain at the time of measurement [73] and epigenetic changes associated with SSRI administration to neonatal or adult rats have been reported [74] [75] [76]. "
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    ABSTRACT: Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.
    Full-text · Article · Jul 2015 · Prostaglandins Leukotrienes and Essential Fatty Acids
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    • "See also Figure S8. Neuron 86, 1–14, May 6, 2015 ª2015 Elsevier Inc. 9 Please cite this article in press as: Nautiyal et al., Distinct Circuits Underlie the Effects of 5-HT1B Receptors on Aggression and Impulsivity, Neuron (2015), adult phenotypes related to psychiatric disorders, including anxiety , depression, aggression, and antisocial personality disorder (Ansorge et al., 2004; Caspi et al., 2002, 2003; Dodge et al., 1990; Richardson-Jones et al., 2011). Aggressive behavior has been linked to developmental alterations in monoamine levels through disruptions in monoamine oxidase A (MAOA) activity. "
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    ABSTRACT: Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulates impulsive behavior during adulthood. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Neuron
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