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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    • "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.
    Prostaglandins Leukotrienes and Essential Fatty Acids 07/2015; DOI:10.1016/j.plefa.2015.07.002 · 2.35 Impact Factor
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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.
    Neuron 04/2015; 86(3). DOI:10.1016/j.neuron.2015.03.041 · 15.05 Impact Factor
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    • "Rodent studies show that pharmacological or genetic manipulation of the developing 5-HT system produces lifelong behavioral alterations (Maciag et al., 2006a; Ansorge et al., 2008; Noorlander et al., 2008; Popa et al., 2008). For example, early-life exposure to tricyclic antidepressants or different types of SSRIs produces adult behavioral abnormalities that resemble human depression, including increased Forced Swim Test (FST) immobility, enhanced anxiety-like behavior, anhedonia , perturbed sleep, and diminished sexual performance (Mirmiqran et al., 1981; Hilakivi and Hilakivi, 1987; Vogel et al., 1990; Velazquez-Moctezuma and Diaz Ruiz, 1992; Hansen et al., 1997; Ansorge et al., 2004, 2008; Maciag et al., 2006a; Hartley et al., 2008; Popa et al., 2008; Simpson et al., 2011). Importantly, these behavioral effects are reasonably consistent across several studies, regardless of the specific SSRI or tricyclic antidepressant used. "
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    ABSTRACT: Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10–20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children’s developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers’ anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10 mg/kg/day p.o.) to examine its effects on offspring’s emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams’ pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim Test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7–21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.
    Neuroscience 11/2014; 284. DOI:10.1016/j.neuroscience.2014.10.044 · 3.36 Impact Factor
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