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Risso B, Miglioli A, Balbi T, Dumollard R, Canesi L. Molecular basis for the effects of SSRIs in non-target aquatic invertebrates: A case study with Mytilus galloprovincialis early larvae. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2025; 282:107306. [PMID: 40068373 DOI: 10.1016/j.aquatox.2025.107306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/17/2025] [Accepted: 02/28/2025] [Indexed: 04/05/2025]
Abstract
Selective Serotonin Reuptake Inhibitors (SSRIs) are among the most prescribed antidepressants, whose increasing consumption results in a continuous discharge into aquatic compartments, where they are detected at ng-µg/L levels. Whilst designed to modulate endogenous levels of circulating Serotonin (5-HT) in humans by selectively interfering with serotonin reuptake transporters (SERTs), SSRIs have been shown to induce a variety of adverse effects in non-target species, including aquatic invertebrates. In bivalve molluscs, adult exposure to environmental concentrations of SSRIs results in tissue bioaccumulation and induces different biomarker responses. However, the effects were not related to the mechanisms of action of SSRIs, due to poor knowledge of their direct molecular targets, SERT in particular. Much less information is available in embryo-larval stages. In this work, the effects of different SSRIs (Fluoxetine, Citalopram, Sertraline, 1-100 µg/L) were compared in the model of Mytilus galloprovincialis embryo-larval development. SSRIs showed small or no effects on normal larval development at 48 h post fertilization (hpf). The possible direct or indirect molecular targets of SSRIs were thus investigated in mussel larvae. Two conserved SERT sequences, SERT1-like and SERT2-like, were identified in M. galloprovincialis genome: their developmental expression showed increased transcription only from 44 and 20 hpf, respectively. A much higher and earlier expression (from 12 hpf) was observed for TPH (Tryptophan Hydroxylase), the rate limiting enzyme in 5-HT synthesis. Double in situ Hybridization Chain Reaction (HCR) showed partial colocalisation of TPH with SERT1-like and SERT2-like transcripts in 48 hpf larvae. At this stage, SSRIs induced a small but significant decrease in the number of TPH-positive cells. Finally, 19 Nose Resistance to Fluoxetine (nrf) sequences were identified, that were highly expressed across all early stages (0-48 hpf). At 48 hpf, nrf expression was associated with the digestive system. The results represent the first data on the establishment of the serotonergic system in mussel early larvae, representing the molecular basis for understanding the effects of SSRIs and their mechanisms of action in model non-target marine invertebrates.
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Affiliation(s)
- Beatrice Risso
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genova, Italy, Corso Europa 26, 16132 Genova, Italy; Institut de la Mer de Villefranche (IMEV), Laboratoire de Biologie du Développement de Villefranche-sur-Mer (LBDV), 181 Chemin du Lazaret, 06230 Villefranche-sur-Mer, France.
| | - Angelica Miglioli
- Institut de la Mer de Villefranche (IMEV), Laboratoire de Biologie du Développement de Villefranche-sur-Mer (LBDV), 181 Chemin du Lazaret, 06230 Villefranche-sur-Mer, France
| | - Teresa Balbi
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genova, Italy, Corso Europa 26, 16132 Genova, Italy; National Biodiversity Future Centre, 90133, Palermo, Italy
| | - Rémi Dumollard
- Institut de la Mer de Villefranche (IMEV), Laboratoire de Biologie du Développement de Villefranche-sur-Mer (LBDV), 181 Chemin du Lazaret, 06230 Villefranche-sur-Mer, France
| | - Laura Canesi
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genova, Italy, Corso Europa 26, 16132 Genova, Italy; National Biodiversity Future Centre, 90133, Palermo, Italy.
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Hayat K, Zheng R, Wang T, Al-Zahrani M, Zeng L, Ye Z, Sajer BH, Pan J. Sustainable poultry practices: integrating green light interventions to control pecking in chicken. BMC Vet Res 2024; 20:433. [PMID: 39342335 PMCID: PMC11437798 DOI: 10.1186/s12917-024-04264-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/03/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND The present study aimed to investigate the impact of the light-emitting diode (LED) green light alone or in combination with melatonin on pecking-related hormone regulation during incubation under normal and under hormonal stress conditions in breeder eggs. This study was divided into 2 experiments: In the first experiment effect of LED green light incubation on pecking-related hormones under normal conditions, on Hy-line brown (low pecking phenotype) and Roman pink (high pecking phenotype) eggs were tested. The 296 eggs of each strain were divided into two groups: LED green light incubation and dark incubation (control), each containing four replicates (37 eggs/replicate). The second experiment was conducted to evaluate the effect of LED green light incubation alone or in combination with melatonin under hormonal stress conditions on Roman pink eggs. A total of 704 Roman pink eggs were taken and divided into four groups, each consisting of 176 eggs. Each group was further divided into 2 subgroups, LED green light-regulated incubation and dark incubation with 88 eggs per subgroup, having 4 replicates of 22 eggs each. The groups were as follows: corticosterone solution injection (CI), corticosterone + melatonin mixed solution injection (CMI), Phosphate buffer solution injection (PI), and no injection (UI). RESULTS Results of the first experiment revealed a higher level of serotonin hormone and lower corticosterone hormone in Hy-Line brown embryos compared to Roman pink embryos during dark incubation. The LED green light incubation significantly (P < 0.05) increased the level of 5-HT while decreasing the CORT level in Roman pink embryos indicating its regulatory effect on pecking-related hormones. Results of the second experiment showed that LED green light incubation significantly (P < 0.05) alleviated the CORT-induced hyperactivity of plasma 5-HT in Roman pink embryos. Furthermore, Melatonin (MLT) injection and LED green light together significantly (P < 0.05) reduced the hormonal stress caused by corticosterone injection in the eggs. CONCLUSIONS Overall, the LED green light regulatory incubation demonstrated a regulatory effect on hormones that influence pecking habits. Additionally, when coupled with MLT injection, it synergistically mitigated hormonal stress in the embryos. So, LED green light incubation emerged as a novel method to reduce the damaging pecking habits of poultry birds.
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Affiliation(s)
- Khwar Hayat
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
- Ministry of Agriculture and Rural Affairs, Key Laboratory of Intelligent Equipment and Robotics for Agriculture of Zhejiang Province, Hangzhou, 310058, China
| | - Rongjin Zheng
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
- Ministry of Agriculture and Rural Affairs, Key Laboratory of Intelligent Equipment and Robotics for Agriculture of Zhejiang Province, Hangzhou, 310058, China
| | - Tao Wang
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
- Ministry of Agriculture and Rural Affairs, Key Laboratory of Intelligent Equipment and Robotics for Agriculture of Zhejiang Province, Hangzhou, 310058, China
| | - Majid Al-Zahrani
- Biological Science Department, College of Science and Art, King Abdulaziz University, Rabigh, Saudi Arabia
| | - Li Zeng
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
- Ministry of Agriculture and Rural Affairs, Key Laboratory of Intelligent Equipment and Robotics for Agriculture of Zhejiang Province, Hangzhou, 310058, China
| | - Zunzhong Ye
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
- Ministry of Agriculture and Rural Affairs, Key Laboratory of Intelligent Equipment and Robotics for Agriculture of Zhejiang Province, Hangzhou, 310058, China
| | - Bayan H Sajer
- Biology Department, Faculty of Science, King Abdul Aziz University, Jeddah, Saudi Arabia
- Immunology Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jinming Pan
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China.
- Ministry of Agriculture and Rural Affairs, Key Laboratory of Intelligent Equipment and Robotics for Agriculture of Zhejiang Province, Hangzhou, 310058, China.
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Adibi JJ, Zhao Y, Koistinen H, Mitchell RT, Barrett ES, Miller R, O'Connor TG, Xun X, Liang HW, Birru R, Smith M, Moog NK. Molecular pathways in placental-fetal development and disruption. Mol Cell Endocrinol 2024; 581:112075. [PMID: 37852527 PMCID: PMC10958409 DOI: 10.1016/j.mce.2023.112075] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/11/2023] [Accepted: 09/24/2023] [Indexed: 10/20/2023]
Abstract
The first trimester of pregnancy ranks high in priority when minimizing harmful exposures, given the wide-ranging types of organogenesis occurring between 4- and 12-weeks' gestation. One way to quantify potential harm to the fetus in the first trimester is to measure a corollary effect on the placenta. Placental biomarkers are widely present in maternal circulation, cord blood, and placental tissue biopsied at birth or at the time of pregnancy termination. Here we evaluate ten diverse pathways involving molecules expressed in the first trimester human placenta based on their relevance to normal fetal development and to the hypothesis of placental-fetal endocrine disruption (perturbation in development that results in abnormal endocrine function in the offspring), namely: human chorionic gonadotropin (hCG), thyroid hormone regulation, peroxisome proliferator activated receptor protein gamma (PPARγ), leptin, transforming growth factor beta, epiregulin, growth differentiation factor 15, small nucleolar RNAs, serotonin, and vitamin D. Some of these are well-established as biomarkers of placental-fetal endocrine disruption, while others are not well studied and were selected based on discovery analyses of the placental transcriptome. A literature search on these biomarkers summarizes evidence of placenta-specific production and regulation of each biomarker, and their role in fetal reproductive tract, brain, and other specific domains of fetal development. In this review, we extend the theory of fetal programming to placental-fetal programming.
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Affiliation(s)
- Jennifer J Adibi
- Department of Epidemiology, University of Pittsburgh School of Public Health, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Yaqi Zhao
- St. Jude's Research Hospital, Memphis, TN, USA
| | - Hannu Koistinen
- Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
| | - Rod T Mitchell
- Department of Paediatric Endocrinology, Royal Hospital for Children and Young People, Edinburgh BioQuarter, Edinburgh, UK
| | - Emily S Barrett
- Environmental and Population Health Bio-Sciences, Rutgers University School of Public Health, Piscataway, NJ, USA
| | - Richard Miller
- Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA
| | - Thomas G O'Connor
- Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, USA
| | - Xiaoshuang Xun
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Hai-Wei Liang
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Rahel Birru
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Megan Smith
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nora K Moog
- Department of Medical Psychology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Yenkoyan K, Mkhitaryan M, Bjørklund G. Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review. Curr Med Chem 2024; 31:2345-2360. [PMID: 38204225 DOI: 10.2174/0109298673252471231121045529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 10/14/2023] [Accepted: 10/19/2023] [Indexed: 01/12/2024]
Abstract
Existing evidence indicates that environmental factors might contribute up to 50% of the variance in autism spectrum disorder (ASD) risk. This structured narrative review offers a comprehensive synthesis of current knowledge on environmental risk factors in ASD, including evaluation of conflicting evidence, exploration of underlying mechanisms, and suggestions for future research directions. Analysis of diverse epidemiological investigations indicates that certain environmental factors, including advanced parental age, preterm birth, delivery complications, and exposure to toxic metals, drugs, air pollutants, and endocrine-disrupting chemicals, are linked to an increased ASD risk through various mechanisms such as oxidative stress, inflammation, hypoxia, and its consequences, changes in neurotransmitters, disruption of signaling pathways and some others. On the other hand, pregnancy-related factors such as maternal diabetes, maternal obesity, and caesarian section show a weaker association with ASD risk. At the same time, other environmental factors, such as vaccination, maternal smoking, or alcohol consumption, are not linked to the risk of ASD. Regarding nutritional elements data are inconclusive. These findings highlight the significance of environmental factors in ASD etiology and emphasize that more focused research is needed to target the risk factors of ASD. Environmental interventions targeting modifiable risk factors might offer promising avenues for ASD prevention and treatment.
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Affiliation(s)
| | - Meri Mkhitaryan
- Neuroscience Laboratory, Cobrain Center, YSMU, Yerevan, 0025, Armenia
| | - Geir Bjørklund
- Department of Research, Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
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Long DR, Kinser A, Olalde-Welling A, Brewer L, Lim J, Matheny D, Long B, Roossien DH. 5-HT1A regulates axon outgrowth in a subpopulation of Drosophila serotonergic neurons. Dev Neurobiol 2023; 83:268-281. [PMID: 37714743 DOI: 10.1002/dneu.22928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/17/2023]
Abstract
Serotonergic neurons produce extensively branched axons that fill most of the central nervous system, where they modulate a wide variety of behaviors. Many behavioral disorders have been correlated with defective serotonergic axon morphologies. Proper behavioral output therefore depends on the precise outgrowth and targeting of serotonergic axons during development. To direct outgrowth, serotonergic neurons utilize serotonin as a signaling molecule prior to it assuming its neurotransmitter role. This process, termed serotonin autoregulation, regulates axon outgrowth, branching, and varicosity development of serotonergic neurons. However, the receptor that mediates serotonin autoregulation is unknown. Here we asked if serotonin receptor 5-HT1A plays a role in serotonergic axon outgrowth and branching. Using cultured Drosophila serotonergic neurons, we found that exogenous serotonin reduced axon length and branching only in those expressing 5-HT1A. Pharmacological activation of 5-HT1A led to reduced axon length and branching, whereas the disruption of 5-HT1A rescued outgrowth in the presence of exogenous serotonin. Altogether this suggests that 5-HT1A is a serotonin autoreceptor in a subpopulation of serotonergic neurons and initiates signaling pathways that regulate axon outgrowth and branching during Drosophila development.
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Affiliation(s)
- Delaney R Long
- Department of Biology, Ball State University, Muncie, Indiana, USA
| | - Ava Kinser
- Department of Biology, Ball State University, Muncie, Indiana, USA
| | | | - Luke Brewer
- Department of Biology, Ball State University, Muncie, Indiana, USA
| | - Juri Lim
- Department of Biology, Ball State University, Muncie, Indiana, USA
| | - Dayle Matheny
- Department of Biology, Ball State University, Muncie, Indiana, USA
| | - Breanna Long
- Department of Biology, Ball State University, Muncie, Indiana, USA
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Domingues RR, Wiltbank MC, Hernandez LL. Maternal serotonin: implications for the use of selective serotonin reuptake inhibitors during gestation†. Biol Reprod 2023; 109:17-28. [PMID: 37098165 PMCID: PMC10344603 DOI: 10.1093/biolre/ioad046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 04/27/2023] Open
Abstract
Maternal use of antidepressants has increased throughout the last decades; selective serotonin reuptake inhibitors (SSRI) are the most prescribed antidepressants. Despite the widespread use of SSRI by women during reproductive age and pregnant women, an increasing amount of research warns of possible detrimental effects of maternal use of SSRI during pregnancy including low birthweight/small for gestational age and preterm birth. In this review, we revisited the impact of maternal use of SSRI during pregnancy, its impact on serotonin homeostasis in the maternal and fetal circulation and the placenta, and its impact on pregnancy outcomes-particularly intrauterine growth restriction and preterm birth. Maternal use of SSRI increases maternal and fetal serotonin. The increase in maternal circulating serotonin and serotonin signaling likely promotes vasoconstriction of the uterine and placental vascular beds decreasing blood perfusion to the uterus and consequently to the placenta and fetus with potential impact on placental function and fetal development. Several adverse pregnancy outcomes are similar between women, sheep, and rodents (decreased placental size, decreased birthweight, shorter gestation length/preterm birth, neonatal morbidity, and mortality) highlighting the importance of animal studies to assess the impacts of SSRI. Herein, we address the complex interactions between maternal SSRI use during gestation, circulating serotonin, and the regulation of blood perfusion to the uterus and fetoplacental unit, fetal growth, and pregnancy complications.
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Affiliation(s)
- Rafael R Domingues
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Milo C Wiltbank
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Laura L Hernandez
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Picone M, Distefano GG, Zangrando R, Gambaro A, Volpi Ghirardini A. Neonicotinoids and pharmaceuticals in hair of the Red fox (Vulpes vulpes) from the Cavallino-Treporti peninsula, Italy. ENVIRONMENTAL RESEARCH 2023; 228:115837. [PMID: 37028535 DOI: 10.1016/j.envres.2023.115837] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/22/2023] [Accepted: 04/01/2023] [Indexed: 05/16/2023]
Abstract
Neonicotinoids (NEOs) and active pharmaceuticals ingredients (API) are contaminants widely diffused worldwide, causing increasing concern for potential adverse effects on wildlife. However, research on these contaminants have focused on target and non-target invertebrates, while information on potential effects in terrestrial mammals is lacking. We performed preliminary non-invasive monitoring of NEOs and API in a suburban and agricultural area using hair of the Red fox. The Red fox is a widely diffused mesopredator in Europe, and its plasticity in feeding habits makes it an excellent indicator for assessing exposure to environmental contamination. We observed the presence of NEOs in many Red fox hair samples (n = 11), including imidacloprid (IMI), acetamiprid (ACE), and clothianidin (CLO). The highest quantified concentrations were 6.4 ng g-1 dry weight (dw), 6.7 ng g-1 dw, and 0.9 ng g-1 dw for IMI, ACE, and CLO, respectively. The targeted APIs included non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants. APIs were less frequently detected than NEOs, and the compounds with the highest prevalence were the NSAID ketoprofen (36%), the antidepressant sertraline (36%), and its active metabolite norsertraline (27%). The presence of human pharmaceuticals such as the NSAID ibuprofen and the antidepressants sertraline, fluoxetine, and their active metabolites norsertraline and norfluoxetine suggest environmental contamination due to untreated and partially treated wastewater discharged in surface waters and soils of the study area. The detection and quantification of ketoprofen and flunixin also suggest the possible use of contaminated manure on farmland. Findings indicate that hair may be used for monitoring environmental exposure to NEOs and provide evidence that hair is a good marker of exposure for antidepressants and certain NSAIDs, including ibuprofen, ketoprofen, and flunixin.
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Affiliation(s)
- Marco Picone
- Department of Environmental Sciences, Informatic, and Statistics, Ca' Foscari University Venice, Via Torino 155, 30172, Venezia-Mestre, Italy.
| | - Gabriele Giuseppe Distefano
- Department of Environmental Sciences, Informatic, and Statistics, Ca' Foscari University Venice, Via Torino 155, 30172, Venezia-Mestre, Italy
| | - Roberta Zangrando
- National Council for the Research - Institute of Polar Sciences, Via Torino 155, 30172, Venezia-Mestre, Italy
| | - Andrea Gambaro
- Department of Environmental Sciences, Informatic, and Statistics, Ca' Foscari University Venice, Via Torino 155, 30172, Venezia-Mestre, Italy; National Council for the Research - Institute of Polar Sciences, Via Torino 155, 30172, Venezia-Mestre, Italy
| | - Annamaria Volpi Ghirardini
- Department of Environmental Sciences, Informatic, and Statistics, Ca' Foscari University Venice, Via Torino 155, 30172, Venezia-Mestre, Italy
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Jadhav VV, Han J, Fasina Y, Harrison SH. Connecting gut microbiomes and short chain fatty acids with the serotonergic system and behavior in Gallus gallus and other avian species. Front Physiol 2022; 13:1035538. [PMID: 36406988 PMCID: PMC9667555 DOI: 10.3389/fphys.2022.1035538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/03/2022] [Indexed: 12/05/2022] Open
Abstract
The chicken gastrointestinal tract has a diverse microbial community. There is increasing evidence for how this gut microbiome affects specific molecular pathways and the overall physiology, nervous system and behavior of the chicken host organism due to a growing number of studies investigating conditions such as host diet, antibiotics, probiotics, and germ-free and germ-reduced models. Systems-level investigations have revealed a network of microbiome-related interactions between the gut and state of health and behavior in chickens and other animals. While some microbial symbionts are crucial for maintaining stability and normal host physiology, there can also be dysbiosis, disruptions to nutrient flow, and other outcomes of dysregulation and disease. Likewise, alteration of the gut microbiome is found for chickens exhibiting differences in feather pecking (FP) behavior and this alteration is suspected to be responsible for behavioral change. In chickens and other organisms, serotonin is a chief neuromodulator that links gut microbes to the host brain as microbes modulate the serotonin secreted by the host's own intestinal enterochromaffin cells which can stimulate the central nervous system via the vagus nerve. A substantial part of the serotonergic network is conserved across birds and mammals. Broader investigations of multiple species and subsequent cross-comparisons may help to explore general functionality of this ancient system and its increasingly apparent central role in the gut-brain axis of vertebrates. Dysfunctional behavioral phenotypes from the serotonergic system moreover occur in both birds and mammals with, for example, FP in chickens and depression in humans. Recent studies of the intestine as a major site of serotonin synthesis have been identifying routes by which gut microbial metabolites regulate the chicken serotonergic system. This review in particular highlights the influence of gut microbial metabolite short chain fatty acids (SCFAs) on the serotonergic system. The role of SCFAs in physiological and brain disorders may be considerable because of their ability to cross intestinal as well as the blood-brain barriers, leading to influences on the serotonergic system via binding to receptors and epigenetic modulations. Examinations of these mechanisms may translate into a more general understanding of serotonergic system development within chickens and other avians.
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Affiliation(s)
- Vidya V. Jadhav
- Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, United States
| | - Jian Han
- Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, United States
| | - Yewande Fasina
- Department of Animal Sciences, North Carolina Agricultural and Technical State University, Greensboro, NC, United States,*Correspondence: Yewande Fasina, ; Scott H. Harrison,
| | - Scott H. Harrison
- Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, United States,*Correspondence: Yewande Fasina, ; Scott H. Harrison,
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Zusman EZ, Lavu A, Pawliuk C, Pawluski J, Hutchison SM, Platt RW, Oberlander TF. Associations Between Prenatal Exposure to Serotonergic Medications and Biobehavioral Stress Regulation: Protocol for a Systematic Review and Meta-analysis. JMIR Res Protoc 2022; 11:e33363. [PMID: 35343913 PMCID: PMC9002587 DOI: 10.2196/33363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Up to 20% of mothers experience antenatal depression and approximately 30% of these women are treated with serotonergic psychotropic pharmacological therapy during pregnancy. Serotonergic antidepressants readily cross the placenta and the fetal blood-brain barrier, altering central synaptic serotonin signaling and potentially altering serotonin levels in the developing fetal brain. OBJECTIVE The aim of this study is to assess the impact of prenatal exposure to serotonergic antidepressants, accounting for maternal mood disturbances, on markers of stress regulation during childhood. METHODS We will follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and will search MEDLINE, Embase, CINAHL, PsycINFO, and ClinicalTrials.gov for full-length studies that assessed physiological (eg, cortisol level, heart rate variability, salivary amylase, pupillary size, C-reactive protein) indices of stress regulation in children of pregnant people who were treated with a serotonergic antidepressant at any point during pregnancy. We will assess the quality of observational studies using the Newcastle-Ottawa Scale and the quality of experimental studies using the Cochrane risk-of-bias tool. When possible, we will conduct a random-effects meta-analysis. If meta-analysis is not possible, we will conduct a narrative review. If a sufficient number of studies are found, we will perform subgroup analysis and assess outcomes measured by drug class, dose, trimester of exposure, and child's age and gender. RESULTS We registered our review protocol with PROSPERO (International Prospective Register of Systematic Reviews; CRD42021275750), completed the literature search, and initiated title and abstract review in August 2021. We expect to finalize this review by April 2022. CONCLUSIONS Findings should identify the impact of prenatal antidepressant effects on stress regulation and distinguish it from the impact of prenatal exposure to maternal mood disturbances. This review should inform decisions about serotonergic antidepressant use during pregnancy. TRIAL REGISTRATION PROSPERO CRD42021275750; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=275750. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/33363.
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Affiliation(s)
- Enav Z Zusman
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, BC, Canada
- British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Alekhya Lavu
- College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada
| | - Colleen Pawliuk
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Jodi Pawluski
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Sarah M Hutchison
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Robert W Platt
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
- Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Tim F Oberlander
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
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Tokariev A, Oberlander VC, Videman M, Vanhatalo S. Cortical Cross-Frequency Coupling Is Affected by in utero Exposure to Antidepressant Medication. Front Neurosci 2022; 16:803708. [PMID: 35310093 PMCID: PMC8927083 DOI: 10.3389/fnins.2022.803708] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/27/2022] [Indexed: 11/24/2022] Open
Abstract
Up to five percent of human infants are exposed to maternal antidepressant medication by serotonin reuptake inhibitors (SRI) during pregnancy, yet the SRI effects on infants’ early neurodevelopment are not fully understood. Here, we studied how maternal SRI medication affects cortical frequency-specific and cross-frequency interactions estimated, respectively, by phase-phase correlations (PPC) and phase-amplitude coupling (PAC) in electroencephalographic (EEG) recordings. We examined the cortical activity in infants after fetal exposure to SRIs relative to a control group of infants without medical history of any kind. Our findings show that the sleep-related dynamics of PPC networks are selectively affected by in utero SRI exposure, however, those alterations do not correlate to later neurocognitive development as tested by neuropsychological evaluation at two years of age. In turn, phase-amplitude coupling was found to be suppressed in SRI infants across multiple distributed cortical regions and these effects were linked to their neurocognitive outcomes. Our results are compatible with the overall notion that in utero drug exposures may cause subtle, yet measurable changes in the brain structure and function. Our present findings are based on the measures of local and inter-areal neuronal interactions in the cortex which can be readily used across species, as well as between different scales of inspection: from the whole animals to in vitro preparations. Therefore, this work opens a framework to explore the cellular and molecular mechanisms underlying neurodevelopmental SRI effects at all translational levels.
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Affiliation(s)
- Anton Tokariev
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- *Correspondence: Anton Tokariev,
| | - Victoria C. Oberlander
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Department of Computer Science, Aalto University, Espoo, Finland
| | - Mari Videman
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Department of Pediatric Neurology, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Sampsa Vanhatalo
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- Department of Physiology, University of Helsinki, Helsinki, Finland
- Sampsa Vanhatalo,
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11
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Long-term effects of pre-gestational stress and perinatal venlafaxine treatment on neurobehavioral development of female offspring. Behav Brain Res 2020; 398:112944. [PMID: 33017639 DOI: 10.1016/j.bbr.2020.112944] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 09/24/2020] [Accepted: 09/26/2020] [Indexed: 02/08/2023]
Abstract
Preclinical studies suggest that stress-related disorders even prior gestation can cause long-term changes at the level of neurobehavioral adaptations. Therefore, it is critical to consider undergoing antidepressant therapy which could reverse the negative consequences in the offspring. Venlafaxine is widely used in clinical practice; however insufficient amount of well-controlled studies verified the safety of venlafaxine therapy during gestation and lactation. The aim of this work was to investigate the effects of perinatal venlafaxine therapy on selected neurobehavioral variables in mothers and their female offspring using a model of maternal adversity. Pre-gestational stressed and non-stressed Wistar rat dams were treated with either venlafaxine (10 mg/kg/day) or vehicle during pregnancy and lactation. We have shown that pre-gestational stress decreased the number of pups with a significant reduction in the number of males but not females. Furthermore, we found that offspring of stressed and treated mothers exhibited anxiogenic behavior in juvenile and adolescent age. However, during adulthood pre-gestational stress significantly increased anxiety-like behavior of female, with venlafaxine treatment normalizing the state to control levels. Additionally, we found that even maternal stress prior gestation can have long-term impact on adult number of hippocampal immature neurons of the female offspring. A number of questions related to the best treatment options for maternal depression still remains, however present data may provide greater insight into the possible outcomes associated with perinatal venlafaxine therapy.
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12
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van der Veere CN, de Vries NKS, van Braeckel KNJA, Bos AF. Intra-uterine exposure to selective serotonin reuptake inhibitors (SSRIs), maternal psychopathology, and neurodevelopment at age 2.5years - Results from the prospective cohort SMOK study. Early Hum Dev 2020; 147:105075. [PMID: 32504880 DOI: 10.1016/j.earlhumdev.2020.105075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 05/09/2020] [Accepted: 05/15/2020] [Indexed: 11/26/2022]
Abstract
BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 2-8% during pregnancy. Whether prenatal exposure to SSRIs has long-term effects on the children's development is unknown. AIM The aim of this study was to determine the effect of prenatal exposure to SSRIs on children's cognitive, motor, and behavioral outcomes at 2.5 years, adjusted for maternal depression and anxiety. METHODS In a prospective, longitudinal cohort-study we included 111 pregnant women treated either or not with an SSRI. We examined cognitive and motor development of their children at 2.5 years, using the Bayley Scale of Infant and Toddler Development, 3rd Edition, and measured emotional and behavioral problems using the parent-rated Child Behavior Checklist (CBCL). Maternal depression and anxiety was determined during pregnancy and at the children's assessment. Differences of normed cognitive, motor, and behavioral scores between SSRI-exposed and non-SSRI-exposed children were tested using multiple linear regression analyses. RESULTS We examined 102 children. SSRI-exposed children had lower scaled scores on cognition and gross motor development than non-SSRI-exposed children: 9.0 ± 1.4 (mean ± SD) versus 9.9 ± 1.7 [P = 0.004], and 7.9 ± 2.2 versus 9.0 ± 2.5 [P = 0.01], respectively. Differences remained significant after adjusting for maternal depression and anxiety and other confounders in various models (mean difference for cognition 0.8 to 0.9 points, for gross motor 1.1 to 1.2 points). Only after adjusting for severity of maternal anxiety, differences in gross motor scores lost significance. CONCLUSIONS Prenatal exposure to SSRIs is associated with poorer cognitive and gross motor development of the children at 2.5 years. Effects on gross motor development disappeared after correction for severity of maternal anxiety.
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Affiliation(s)
- Christine N van der Veere
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands.
| | - Nathalie K S de Vries
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands
| | | | - Arend F Bos
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands
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13
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Liu Q, Chen MX, Sun L, Wallis CU, Zhou JS, Ao LJ, Li Q, Sham PC. Rational use of mesenchymal stem cells in the treatment of autism spectrum disorders. World J Stem Cells 2019; 11:55-72. [PMID: 30842805 PMCID: PMC6397804 DOI: 10.4252/wjsc.v11.i2.55] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/30/2018] [Accepted: 01/23/2019] [Indexed: 02/06/2023] Open
Abstract
Autism and autism spectrum disorders (ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD. Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review will focus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.
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Affiliation(s)
- Qiang Liu
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Mo-Xian Chen
- School of Rehabilitation, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Lin Sun
- Department of Psychology, Weifang Medical University, Weifang 261053, Shandong Province, China
| | - Chloe U Wallis
- Medical Sciences Division, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Jian-Song Zhou
- Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Li-Juan Ao
- School of Rehabilitation, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Qi Li
- Department of Psychiatry, the University of Hong Kong, Hong Kong, China
| | - Pak C Sham
- Department of Psychiatry, the University of Hong Kong, Hong Kong, China
- State Key Laboratory of Brain and Cognitive Sciences, Center for Genomic Sciences, the University of Hong Kong, Hong Kong, China
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14
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de Haas EN, van der Eijk JA. Where in the serotonergic system does it go wrong? Unravelling the route by which the serotonergic system affects feather pecking in chickens. Neurosci Biobehav Rev 2018; 95:170-188. [PMID: 30055196 DOI: 10.1016/j.neubiorev.2018.07.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 12/16/2022]
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15
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Davis EP, Hankin BL, Swales DA, Hoffman MC. An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression? Dev Psychopathol 2018; 30:787-806. [PMID: 30068416 PMCID: PMC7040571 DOI: 10.1017/s0954579418000470] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Maternal depression is one of the most common prenatal complications, and prenatal maternal depression predicts many child psychopathologies. Here, we apply the fetal programming hypothesis as an organizational framework to address the possibility that fetal exposure to maternal depressive symptoms during pregnancy affects fetal development of vulnerabilities and risk mechanisms, which enhance risk for subsequent psychopathology. We consider four candidate pathways through which maternal prenatal depression may affect the propensity of offspring to develop later psychopathology across the life span: brain development, physiological stress regulation (hypothalamic-pituitary-adrenocortical axis), negative emotionality, and cognitive (effortful) control. The majority of past research has been correlational, so potential causal conclusions have been limited. We describe an ongoing experimental test of the fetal programming influence of prenatal maternal depressive symptoms using a randomized controlled trial design. In this randomized controlled trial, interpersonal psychotherapy is compared to enhanced usual care among distressed pregnant women to evaluate whether reducing prenatal maternal depressive symptoms has a salutary impact on child ontogenetic vulnerabilities and thereby reduces offspring's risk for emergence of later psychopathology.
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Affiliation(s)
- Elysia Poggi Davis
- Department of Psychology, University of Denver, Denver, Colorado
- Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine California
| | - Benjamin L. Hankin
- Department of Psychology, University of Illinois, Urbana Champaign, Illinois
| | | | - M. Camille Hoffman
- University of Colorado School of Medicine, Departments of Obstetrics and Gynecology and Psychiatry, Aurora, CO
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16
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Videman M, Tokariev A, Saikkonen H, Stjerna S, Heiskala H, Mantere O, Vanhatalo S. Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors. Cereb Cortex 2018; 27:3208-3216. [PMID: 27269962 DOI: 10.1093/cercor/bhw153] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Recent experimental animal studies have shown that fetal exposure to serotonin reuptake inhibitors (SRIs) affects brain development. Modern recording methods and advanced computational analyses of scalp electroencephalography (EEG) have opened a possibility to study if comparable changes are also observed in the human neonatal brain. We recruited mothers using SRI during pregnancy (n = 22) and controls (n = 62). Mood and anxiety of mothers, newborn neurology, and newborn cortical function (EEG) were assessed. The EEG parameters were compared between newborns exposed to drugs versus controls, followed by comparisons of newborn EEG features with maternal psychiatric assessments. Neurological assessment showed subtle abnormalities in the SRI-exposed newborns. The computational EEG analyses disclosed a reduced interhemispheric connectivity, lower cross-frequency integration, as well as reduced frontal activity at low-frequency oscillations. These effects were not related to maternal depression or anxiety. Our results suggest that antenatal serotonergic treatment might change newborn brain function in a manner compatible with the recent experimental studies. The present EEG findings suggest links at the level of neuronal activity between human studies and animal experiments. These links will also enable bidirectional translation in future studies on the neuronal mechanisms and long-term neurodevelopmental effects of early SRI exposure.
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Affiliation(s)
- Mari Videman
- Division of Pediatric Neurology, Department of Children and Adolescents.,BABA Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland
| | - Anton Tokariev
- Department of Children's Clinical Neurophysiology, HUS Medical Imaging Center and Children's Hospital.,Department of Biosciences, University of Helsinki, Helsinki, Finland
| | - Heini Saikkonen
- Department of Psychiatry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Susanna Stjerna
- Department of Children's Clinical Neurophysiology, HUS Medical Imaging Center and Children's Hospital
| | - Hannu Heiskala
- Division of Pediatric Neurology, Department of Children and Adolescents
| | - Outi Mantere
- Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland.,Department of Psychiatry, McGill University, Montréal, Canada.,Bipolar Disorders Clinic, Douglas Mental Health University Institute, Montréal, Canada
| | - Sampsa Vanhatalo
- Department of Children's Clinical Neurophysiology, HUS Medical Imaging Center and Children's Hospital
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17
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Healy D, Le Noury J, Mangin D. Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence. INTERNATIONAL JOURNAL OF RISK & SAFETY IN MEDICINE 2017; 28:125-41. [PMID: 27662278 DOI: 10.3233/jrs-160726] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To investigate possible linkages between neurodevelopmental delay and neurodevelopmental spectrum disorders and exposure to medication with effects on serotonin reuptake inhibition during pregnancy. METHODS We systematically reviewed the epidemiological literature for studies bearing on this relationship in children born with neurodevelopmental spectrum disorder and related conditions, as well as animal studies giving serotonin reuptake inhibitors to pregnant animals and in addition reviewed the literature for proposals as to possible mechanisms that might link effects on serotonin reuptake with cognitive changes post-partum.The epidemiological studies were analysed to produce Forest plots to illustrate possible relations. RESULTS The odds ratio of Autistic Spectrum or related Disorders in children born to women taking serotonin reuptake inhibiting antidepressants during pregnancy in case control studies was 1.95 (95% C.I. 1.63, 2.34) and in prospective cohort studies was 1.96 (95% C.I. 1.33, 2.90). CONCLUSIONS There appears to be a link between serotonin reuptake inhibition in pregnancy and developmental delay and spectrum disorders in infancy leading to cognitive difficulties in childhood. More work needs to be done to establish more precisely the nature of the difficulties and possible mechanisms through which this link might be mediated.
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Affiliation(s)
- D Healy
- North Wales Department of Psychological Medicine, Bangor University, Wales, UK
| | - J Le Noury
- North Wales Department of Psychological Medicine, Bangor University, Wales, UK
| | - D Mangin
- David Braley Nancy Gordon Chair in Family Medicine, Department of Family Medicine, McMaster University, Hamilton, ON, Canada
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18
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Andalib S, Emamhadi MR, Yousefzadeh-Chabok S, Shakouri SK, Høilund-Carlsen PF, Vafaee MS, Michel TM. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur Psychiatry 2017; 45:161-166. [PMID: 28917161 DOI: 10.1016/j.eurpsy.2017.06.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 06/01/2017] [Accepted: 06/04/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants used to preclude maternal pregnancy depression. There is a growing body of literature assessing the association of prenatal exposure to SSRIs with autism spectrum disorder (ASD). The present systematic review and meta-analysis reviewed the medical literature and pooled the results of the association of prenatal exposure to SSRIs with ASD. METHODS Published investigations in English by June 2016 with keywords of selective serotonin reuptake inhibitors, SSRI, autism spectrum disorder, ASD, pregnancy, childhood, children, neurodevelopment were identified using databases PubMed and PMC, MEDLINE, EMBASE, SCOPUS, and Google Scholar. Cochran's Q statistic-value (Q), degree of freedom (df), and I2 indices (variation in odds ratio [OR] attributable to heterogeneity) were calculated to analyze the risk of heterogeneity of the within- and between-study variability. Pooled odds ratio (OR) and 95% confidence interval (CI) were reported by a Mantel-Haenszel test. RESULTS There was a non-significant heterogeneity for the included studies ([Q=3.61, df=6, P=0.730], I2=0%). The pooled results showed a significant association between prenatal SSRI exposure and ASD (OR=1.82, 95% CI=1.59-2.10, Z=8.49, P=0.00). CONCLUSION The evidence from the present study suggests that prenatal exposure to SSRIs is associated with a higher risk of ASD.
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Affiliation(s)
- S Andalib
- Neuroscience Research Center, Department of Neurosurgery, Poursina Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
| | - M R Emamhadi
- Brachial Plexus and Peripheral Nerve Injury Center, Guilan University of Medical Sciences, Rasht, Iran
| | - S Yousefzadeh-Chabok
- Neuroscience Research Center, Department of Neurosurgery, Poursina Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - S K Shakouri
- Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - P F Høilund-Carlsen
- Department of Nuclear Medicine, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - M S Vafaee
- Department of Nuclear Medicine, Odense University Hospital, University of Southern Denmark, Odense, Denmark; Department of Psychiatry, Psychiatry Region of Southern, Odense, Denmark; Research Unit of Psychiatry, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Center for Applied Neuroscience, BRIDGE, Odense University Hospital, University of Southern Denmark, Psychiatry in the Region of Southern Denmark, Odense, Denmark; Neurosciences Research Center, Department of Neurology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - T M Michel
- Department of Psychiatry, Psychiatry Region of Southern, Odense, Denmark; Research Unit of Psychiatry, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Center for Applied Neuroscience, BRIDGE, Odense University Hospital, University of Southern Denmark, Psychiatry in the Region of Southern Denmark, Odense, Denmark; Neurosciences Research Center, Department of Neurology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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19
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Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, Park BY, Snyder NW, Schendel D, Volk H, Windham GC, Newschaffer C. The Changing Epidemiology of Autism Spectrum Disorders. Annu Rev Public Health 2017; 38:81-102. [PMID: 28068486 PMCID: PMC6566093 DOI: 10.1146/annurev-publhealth-031816-044318] [Citation(s) in RCA: 589] [Impact Index Per Article: 73.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.
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Affiliation(s)
- Kristen Lyall
- A.J. Drexel Autism Institute, Philadelphia, Pennsylvania 19104;
| | - Lisa Croen
- Kaiser Permanente Division of Research, Oakland, California 94612
| | - Julie Daniels
- Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, North Carolina 27599
| | - M Daniele Fallin
- Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
| | - Christine Ladd-Acosta
- Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
| | - Brian K Lee
- Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia, Pennsylvania 19104
- Department of Medical Epidemiology and Biostatistics and Department of Public Health Sciences, Karolinska Institute, SE 171-77 Stockholm, Sweden
| | - Bo Y Park
- Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
| | | | - Diana Schendel
- Department of Economics and Business, National Centre for Register-Based Research, Aarhus University, DK-8210 Aarhus, Denmark
- Department of Public Health, Section for Epidemiology, Aarhus University, DK-8000 Aarhus, Denmark
- Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Heather Volk
- Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
| | - Gayle C Windham
- California Department of Public Health, Division of Environmental and Occupational Disease Control, Richmond, California 94805
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20
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Making Sense Out of the Controversy: Use of SSRIs in Pregnancy. CURRENT OBSTETRICS AND GYNECOLOGY REPORTS 2016. [DOI: 10.1007/s13669-016-0173-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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21
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Partridge MCA, Salisbury AL, LaGasse LL. Fine Motor Differences and Prenatal Serotonin Reuptake Inhibitors Exposure. J Pediatr 2016; 175:144-149.e1. [PMID: 27215778 PMCID: PMC4981505 DOI: 10.1016/j.jpeds.2016.04.065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 03/07/2016] [Accepted: 04/19/2016] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To examine fine motor differences between preschoolers with prenatal exposure to serotonin reuptake inhibitor (SRI) and children of mothers with major depressive disorder. STUDY DESIGN A subset of children (N = 40) from a larger study on the effects of prenatal SRI and untreated major depressive disorder participated in a kinematic task of visual motor and fine motor functions at ages 4-5 years: exposure to SRI (n = 15), untreated major depressive disorder exposure (n = 10), and the control group (n = 15). The task was to reach and secure a peg, then drop it in a small hole near the start position in the light condition with full visibility or in the glow condition in which a phosphorescent peg glows in the dark. Movement-tracking software measured the positioning of the moving hand and fingers. RESULTS In the glow condition, the group exposed to SRIs had a greater proportion of maximum aperture than the group with major depressive disorder, and the group exposed to SRIs was slower than the group with major depressive disorder to drop the peg into the hole. In the glow condition, the trajectory of the group exposed to SRI was less straight than the group with major depressive disorder, and the group with major depressive disorder had a straighter trajectory than the control group. CONCLUSION This study provides evidence that preschool aged children with prenatal SRI exposure have poorer fine motor and visual-motor control compared with those with prenatal untreated major depressive disorder.
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Affiliation(s)
- Marie-Claire A.E. Partridge
- Department of Neuroscience, Warren Alpert Medical School of Brown University,Brown Center for the Study of Children at Risk,Department of Pediatrics, Women and Infants Hospital of Rhode Island
| | - Amy L. Salisbury
- Brown Center for the Study of Children at Risk,Department of Pediatrics, Warren Alpert Medical School of Brown University, Women & Infants Hospital,Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University,Department of Pediatrics, Women and Infants Hospital of Rhode Island
| | - Linda L. LaGasse
- Brown Center for the Study of Children at Risk,Department of Pediatrics, Warren Alpert Medical School of Brown University, Women & Infants Hospital,Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University,Department of Pediatrics, Women and Infants Hospital of Rhode Island
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22
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Jha SC, Meltzer-Brody S, Steiner RJ, Cornea E, Woolson S, Ahn M, Verde AR, Hamer RM, Zhu H, Styner M, Gilmore JH, Knickmeyer RC. Antenatal depression, treatment with selective serotonin reuptake inhibitors, and neonatal brain structure: A propensity-matched cohort study. Psychiatry Res 2016; 253:43-53. [PMID: 27254086 PMCID: PMC4930375 DOI: 10.1016/j.pscychresns.2016.05.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 05/08/2016] [Accepted: 05/22/2016] [Indexed: 11/17/2022]
Abstract
The aim of this propensity-matched cohort study was to evaluate the impact of prenatal SSRI exposure and a history of maternal depression on neonatal brain volumes and white matter microstructure. SSRI-exposed neonates (n=27) were matched to children of mothers with no history of depression or SSRI use (n=54). Additionally, neonates of mothers with a history of depression, but no prenatal SSRI exposure (n=41), were matched to children of mothers with no history of depression or SSRI use (n=82). Structural magnetic resonance imaging and diffusion weighted imaging scans were acquired with a 3T Siemens Allegra scanner. Global tissue volumes were characterized using an automatic, atlas-moderated expectation maximization segmentation tool. Local differences in gray matter volumes were examined using deformation-based morphometry. Quantitative tractography was performed using an adaptation of the UNC-Utah NA-MIC DTI framework. SSRI-exposed neonates exhibited widespread changes in white matter microstructure compared to matched controls. Children exposed to a history of maternal depression but no SSRIs showed no significant differences in brain development compared to matched controls. No significant differences were found in global or regional tissue volumes. Additional research is needed to clarify whether SSRIs directly alter white matter development or whether this relationship is mediated by depressive symptoms during pregnancy.
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Affiliation(s)
- Shaili C Jha
- Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Samantha Meltzer-Brody
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Rachel J Steiner
- Psychological Sciences, Vanderbilt University, Nasheville, TN 37240, USA
| | - Emil Cornea
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Mihye Ahn
- Department of Mathematics and Statistics, University of Nevada, Reno, NV 89557, USA
| | - Audrey R Verde
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Robert M Hamer
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Hongtu Zhu
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Martin Styner
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - John H Gilmore
- Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Rebecca C Knickmeyer
- Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Gidaya NB, Lee BK, Burstyn I, Yudell M, Mortensen EL, Newschaffer CJ. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. J Autism Dev Disord 2015; 44:2558-67. [PMID: 24803368 DOI: 10.1007/s10803-014-2128-4] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status. There were 1.5 % of cases and 0.7 % of controls exposed to SSRIs during the pregnancy period, and higher effect estimates observed with longer use. We found evidence that in utero exposure to SSRIs increases a child's risk associated with ASD. These results, while adding to the limited knowledge on prenatal pharmacological exposures as potential ASD risk factors, need to be balanced against the benefits of indicated medication use by pregnant mothers.
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Affiliation(s)
- Nicole B Gidaya
- Drexel University, School of Public Health, Nesbitt Hall, 3215 Market Street, Philadelphia, PA, 19104, USA,
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da Silva AI, Braz GRF, Silva-Filho R, Pedroza AA, Ferreira DS, Manhães de Castro R, Lagranha C. Effect of fluoxetine treatment on mitochondrial bioenergetics in central and peripheral rat tissues. Appl Physiol Nutr Metab 2015; 40:565-74. [DOI: 10.1139/apnm-2014-0462] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Recent investigations have focused on the mitochondrion as a direct drug target in the treatment of metabolic diseases (obesity, metabolic syndrome). Relatively few studies, however, have explicitly investigated whether drug therapies aimed at changing behavior by altering central nervous system (CNS) function affect mitochondrial bioenergetics, and none has explored their effect during early neonatal development. The present study was designed to evaluate the effects of chronic treatment of newborn male rats with the selective serotonin reuptake inhibitor fluoxetine on the mitochondrial bioenergetics of the hypothalamus and skeletal muscle during the critical nursing period of development. Male Wistar rat pups received either fluoxetine (Fx group) or vehicle solution (Ct group) from the day of birth until 21 days of age. At 60 days of age, mitochondrial bioenergetics were evaluated. The Fx group showed increased oxygen consumption in several different respiratory states and reduced production of reactive oxygen species, but there was no change in mitochondrial permeability transition pore opening or oxidative stress in either the hypothalamus or skeletal muscle. We observed an increase in glutathione S-transferase activity only in the hypothalamus of the Fx group. Taken together, our results suggest that chronic exposure to fluoxetine during the nursing phase of early rat development results in a positive modulation of mitochondrial respiration in the hypothalamus and skeletal muscle that persists into adulthood. Such long-lasting alterations in mitochondrial activity in the CNS, especially in areas regulating appetite, may contribute to permanent changes in energy balance in treated animals.
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Affiliation(s)
- Aline Isabel da Silva
- Programa de Pós-Graduação em Nutrição, Departamento de Nutrição da Universidade Federal de Pernambuco, Recife, Brazil
- Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, CAV-Federal University of Pernambuco, Brazil
| | - Glauber Ruda Feitoza Braz
- Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, CAV-Federal University of Pernambuco, Brazil
| | - Reginaldo Silva-Filho
- Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, CAV-Federal University of Pernambuco, Brazil
| | - Anderson Apolonio Pedroza
- Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, CAV-Federal University of Pernambuco, Brazil
| | - Diorginis Soares Ferreira
- Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, CAV-Federal University of Pernambuco, Brazil
| | - Raul Manhães de Castro
- Programa de Pós-Graduação em Nutrição, Departamento de Nutrição da Universidade Federal de Pernambuco, Recife, Brazil
| | - Claudia Lagranha
- Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, CAV-Federal University of Pernambuco, Brazil
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25
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De Long NE, Barry EJ, Pinelli C, Wood GA, Hardy DB, Morrison KM, Taylor VH, Gerstein HC, Holloway AC. Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats. Toxicol Appl Pharmacol 2015; 285:32-40. [DOI: 10.1016/j.taap.2015.03.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Revised: 02/12/2015] [Accepted: 03/05/2015] [Indexed: 12/21/2022]
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Changes induced by prenatal stress in behavior and brain morphology: can they be prevented or reversed? ADVANCES IN NEUROBIOLOGY 2015; 10:3-25. [PMID: 25287533 DOI: 10.1007/978-1-4939-1372-5_1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This chapter presents a critical analysis of the behavioral alterations reported in the offspring of women exposed to stress and/or depression during pregnancy and the neurochemical and structural changes underlying them. Among the alterations attributed to prenatal stress in humans and experimental rats of both sexes is impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis, anxiety and exaggerated fear of novelty, and decreased social interaction. Learning and attention deficits are more prevalent in boys and male rats. Fear of novelty and anxiety are associated with enlargement of the amygdala and its corticotropin-releasing factor content, and decreased socialization, with lower oxytocin activity in the amygdala. Learning deficits are associated with a decrease in neurogenesis, dendritic complexity, and spine number in the dorsal hippocampus. Fostering prenatally stressed (PS) pups onto control mothers prevents the dysregulation of the HPA axis and heightened anxiety, indicating a role for postnatal factors in their etiology. By contrast, learning impairment and decreased socialization are not affected by this fostering procedure and are therefore prenatally mediated.In spite of their widespread use in depressed pregnant women, selective serotonin reuptake inhibitor (SSRI) antidepressants do not normalize the behavior of their children. When administered during gestation to stressed rats, SSRIs do not reduce anxiety or learning deficits in their offspring. Moreover, when given to unstressed mothers, SSRIs induce anxiety in the offspring. The detrimental effect of SSRIs may result from inhibition of the serotonin transporter exposing the brain to excess amounts of 5-hydroxytryptamine (5-HT) at a critical time during fetal development.
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Singh M, Singh K, Shukla S, Dikshit M. Assessment of
in‐utero
venlafaxine induced, ROS‐mediated, apoptotic neurodegeneration in fetal neocortex and neurobehavioral sequelae in rat offspring. Int J Dev Neurosci 2014; 40:60-9. [DOI: 10.1016/j.ijdevneu.2014.10.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Revised: 10/16/2014] [Accepted: 10/21/2014] [Indexed: 01/18/2023] Open
Affiliation(s)
- Manish Singh
- Institute of Nano Science and TechnologyMohaliIndia
| | - K.P. Singh
- Neurobiology LabDepartment of ZoologyUniversity of AllahabadAllahabadIndia
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Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Serotonin Hypothesis of Autism: Implications for Selective Serotonin Reuptake Inhibitor Use during Pregnancy. Autism Res 2013; 6:149-68. [DOI: 10.1002/aur.1288] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 02/15/2013] [Indexed: 11/11/2022]
Affiliation(s)
- Rebecca A. Harrington
- Department of Epidemiology; Johns Hopkins Bloomberg School of Public Health; Baltimore; Maryland
| | - Li-Ching Lee
- Department of Epidemiology; Johns Hopkins Bloomberg School of Public Health; Baltimore; Maryland
| | - Rosa M. Crum
- Departments of Epidemiology, Psychiatry, and Mental Health; Johns Hopkins Medical Institutions; Baltimore; Maryland
| | - Andrew W. Zimmerman
- Lurie Center for Autism; Massachusetts General Hospital for Children; Lexington; Massachusetts
| | - Irva Hertz-Picciotto
- Department of Public Health Sciences and the M.I.N.D. Institute; MS1C; University of California, Davis; Davis; California
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29
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Psychiatric neural networks and neuropharmacology: Selected advances and novel implications. Saudi Pharm J 2013; 22:95-100. [PMID: 24648819 DOI: 10.1016/j.jsps.2013.01.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 01/25/2013] [Indexed: 01/13/2023] Open
Abstract
Psychiatric disorders are often considered as simple imbalances between a limited number of cerebral neurotransmitters. In fact, it is more complicated than this "simple approach" and each psychiatric disorder constitutes network dysfunction within which several agents and factors are implicated. Thus, the therapeutical perspectives and implications are as vast and as numerous as the diversity of those network dysfunctions. Furthermore, the description of factors influencing diseases prognoses and treatment efficacy indicates new elements to consider both in therapies and drug researches.
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Abstract
AbstractSerotonin (5HT) is a biologically active amine with diverse roles in the mammalian organism. Developmental alterations in 5HT homeostasis could lead to exposure of the developing brain to non-optimal serotonin concentrations that may result in developmental and behavioral deficits. In order to explore the molecular basis of the effects of developmental disturbances on 5HT metabolism on adult central 5HT homeostasis, observed in our previous studies, we measured changes in gene expression of the neuronal 5HT-regulating proteins in adult animals after perinatal treatment with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25 mg/kg), or monoamine oxidase (MAO) inhibitor tranylcypromine (TCP 2 mg/kg), during the period of the most intensive development of 5HT neurons — from gestational day 12 until postnatal day 21. Adult animals were sacrificed and the relative mRNA levels for tryptophan hydroxylase 2, MAO A, MAO B, receptors 5HT1A and 5HT2A, 5HT transporter (5HTT) and vesicular monoamine transporter (VMAT) were determined in the raphe nuclei region and prefrontal cortex using Real-Time Relative qRT-PCR. In comparison to the saline treated animals, treatment with 5HTP caused mild but significant increase in MAO A and MAO B mRNA abundance. TCP-treated animals, besides an increase in mRNA abundance for both MAO genes, displayed significantly increased 5HTT and VMAT2 mRNA levels and significantly decreased 5HT1A receptor mRNA levels. Our results suggest that perinatal exposure of rats to 5HTP, and especially TCP, induces long-lasting/permanent changes in the expression of 5HT-regulating genes, that presumably underlie 5HT-related neurochemical and behavioral changes in adult animals.
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31
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Sauls K, de Vlaming A, Harris BS, Williams K, Wessels A, Levine RA, Slaugenhaupt SA, Goodwin RL, Pavone LM, Merot J, Schott JJ, Le Tourneau T, Dix T, Jesinkey S, Feng Y, Walsh C, Zhou B, Baldwin S, Markwald RR, Norris RA. Developmental basis for filamin-A-associated myxomatous mitral valve disease. Cardiovasc Res 2012; 96:109-19. [PMID: 22843703 DOI: 10.1093/cvr/cvs238] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
AIMS We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development. METHODS AND RESULTS Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype. CONCLUSIONS These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.
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Affiliation(s)
- Kimberly Sauls
- Department of Regenerative Medicine and Cell Biology, School of Medicine, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA
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32
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Neonatal fluoxetine exposure alters motor performances of adolescent rats. Dev Neurobiol 2012; 72:1122-32. [DOI: 10.1002/dneu.20942] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 06/16/2011] [Accepted: 06/17/2011] [Indexed: 11/07/2022]
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Schaefer TL, Grace CE, Skelton MR, Graham DL, Gudelsky GA, Vorhees CV, Williams MT. Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats. ACS Chem Neurosci 2012; 3:12-21. [PMID: 22582138 DOI: 10.1021/cn2000553] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug's cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.
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Affiliation(s)
- Tori L. Schaefer
- Division of Neurology, Department
of Pediatrics, Cincinnati Children’s Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, United States
| | - Curtis E. Grace
- United States Environmental Protection Agency, Durham, North Carolina 27713, United
States
| | - Matthew R. Skelton
- Division of Neurology, Department
of Pediatrics, Cincinnati Children’s Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, United States
| | - Devon L. Graham
- Vanderbilt University College of Medicine, Nashville, Tennessee 32732, United
States
| | - Gary A. Gudelsky
- James L. Winkle
College of Pharmacy, University of Cincinnati, Ohio 45267-0004, United States
| | - Charles V. Vorhees
- Division of Neurology, Department
of Pediatrics, Cincinnati Children’s Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, United States
| | - Michael T. Williams
- Division of Neurology, Department
of Pediatrics, Cincinnati Children’s Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, United States
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34
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Pawluski JL. Perinatal selective serotonin reuptake inhibitor exposure: impact on brain development and neural plasticity. Neuroendocrinology 2012; 95:39-46. [PMID: 21893935 DOI: 10.1159/000329293] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 04/27/2011] [Indexed: 11/19/2022]
Abstract
Selective serotonin reuptake inhibitor (SSRI) medications are the most common antidepressant treatment used during pregnancy and the postpartum period. Up to 10% of pregnant women are prescribed SSRIs. Serotonin plays an integral part in neurodevelopment, and questions have been raised about the placental transfer of SSRIs and the effects of preventing reuptake of presynaptic serotonin on fetal neurodevelopment. Preclinical data is beginning to document a role of early exposure to SSRIs in long-term developmental outcomes related to a number of brain regions, such as the hippocampus, cortex and cerebellum. To date, the majority of preclinical work has investigated the developmental effects of SSRIs in the offspring of healthy mothers; however, more research is needed on the effects of these medications in the face of maternal adversity. This minireview will highlight emerging evidence from clinical and preclinical studies investigating the impact of perinatal SSRI exposure on brain development and neural plasticity.
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Affiliation(s)
- Jodi L Pawluski
- Department of Neuroscience, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. j.pawluski @ maastrichtuniversity.nl
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35
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Klinger G, Frankenthal D, Merlob P, Diamond G, Sirota L, Levinson-Castiel R, Linder N, Stahl B, Inbar D. Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome. J Perinatol 2011; 31:615-620. [PMID: 21311497 DOI: 10.1038/jp.2010.211] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Revised: 11/28/2010] [Accepted: 12/01/2010] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To assess the long-term neurodevelopment of children exposed in utero to selective serotonin reuptake inhibitors (SSRIs) that developed a neonatal abstinence syndrome (NAS). STUDY DESIGN Neurodevelopmental evaluation was performed at the age of 2 to 6 years. Children who developed NAS were compared with those who did not using univariate and logistic regression analyses. RESULT Thirty children with NAS and 52 without NAS participated in the study. Both groups were similar in mean cognitive ability (106.9±14.0 vs 100.5±14.6, P=0.12) and developmental scores (98.9±11.4 vs 95.7±9.9, P=0.21). However, there was a trend towards small head circumference in the NAS group (20 vs 6%, P=0.068). NAS was associated with an increased risk of social-behavior abnormalities (odds ratio (OR) 3.03, 95% confidence interval (CI) 1.07 to 8.60, P=0.04) and advanced maternal age (OR 1.12, 95% CI 1.00 to 1.25, P=0.04). CONCLUSION Infants who developed NAS had normal cognitive ability, but were at an increased risk for social-behavioral abnormalities. Follow-up evaluation of symptomatic neonates should be considered.
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Affiliation(s)
- G Klinger
- Neonatal Intensive Care Unit, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.
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36
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Klomp A, Tremoleda JL, Wylezinska M, Nederveen AJ, Feenstra M, Gsell W, Reneman L. Lasting effects of chronic fluoxetine treatment on the late developing rat brain: age-dependent changes in the serotonergic neurotransmitter system assessed by pharmacological MRI. Neuroimage 2011; 59:218-26. [PMID: 21840402 DOI: 10.1016/j.neuroimage.2011.07.082] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 07/18/2011] [Accepted: 07/26/2011] [Indexed: 01/26/2023] Open
Abstract
RATIONALE With the growing prevalence of psychotropic drug prescriptions among children and adolescents, the need for studies on lasting effects of drug exposure on the developing brain rises. Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) officially registered to treat major depressive disorder in children. Although various (pre)clinical studies have assessed the (long-term) effects of fluoxetine exposure in the perinatal period and in adulthood, limited data is available on its effects on the developing brain later in life, i.e. during adolescence. OBJECTIVE The present study aimed at investigating the effects of age following chronic SSRI treatment on the central serotonin (5-HT) system. To this end, pharmacological MRI (phMRI) was performed in chronic fluoxetine-treated (5 mg/kg, oral gavage for 3 weeks) juvenile (PND25) and adult rats (PND65) after a 1-week washout period, using an acute fluoxetine challenge (5 mg/kg, i.v.) to trigger the 5-HT system. RESULTS We observed a diminished brain response to the acute challenge in adult treated animals when compared to control animals, whereas this response was increased in juvenile treated rats. As a result, a significant age by treatment interaction effect was seen in several (subcortical) 5-HT related brain regions. CONCLUSION An opposite effect of chronic fluoxetine treatment was seen in the developing brain compared to that in matured brain, as assessed non-invasively using phMRI. These findings most likely reflect neuronal imprinting effects of juvenile SSRI treatment and may underlie emotional disturbances seen in animals and children treated with this drug. Also, our findings suggest that phMRI might be ideally suited to study this important issue in the pediatric population.
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Affiliation(s)
- A Klomp
- Department of Radiology, Academic Medical Centre Amsterdam, Netherlands.
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Wang CC, Borchert A, Ugun-Klusek A, Tang LY, Lui WT, Chu CY, Billett E, Kuhn H, Ufer C. Monoamine oxidase a expression is vital for embryonic brain development by modulating developmental apoptosis. J Biol Chem 2011; 286:28322-30. [PMID: 21697081 DOI: 10.1074/jbc.m111.241422] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression R1 was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium, which coincided with impaired activation of caspases 3 and 9. Moreover, we observed reduced cyclin D1 levels as an indicator of impaired cell proliferation in MAO-A knockdown embryos. This data highlights MAO-A as a vital regulator of embryonic brain development.
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Affiliation(s)
- Chi Chiu Wang
- Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Strasse 16, 13347 Berlin, Germany
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Daws LC, Gould GG. Ontogeny and regulation of the serotonin transporter: providing insights into human disorders. Pharmacol Ther 2011; 131:61-79. [PMID: 21447358 DOI: 10.1016/j.pharmthera.2011.03.013] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Accepted: 03/11/2011] [Indexed: 12/17/2022]
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) was one of the first neurotransmitters for which a role in development was identified. Pharmacological and gene knockout studies have revealed a critical role for 5-HT in numerous processes, including cell division, neuronal migration, differentiation and synaptogenesis. An excess in brain 5-HT appears to be mechanistically linked to abnormal brain development, which in turn is associated with neurological disorders. Ambient levels of 5-HT are controlled by a vast orchestra of proteins, including a multiplicity of pre- and post-synaptic 5-HT receptors, heteroreceptors, enzymes and transporters. The 5-HT transporter (SERT, 5-HTT) is arguably the most powerful regulator of ambient extracellular 5-HT. SERT is the high-affinity uptake mechanism for 5-HT and exerts tight control over the strength and duration of serotonergic neurotransmission. Perturbation of its expression level or function has been implicated in many diseases, prominent among them are psychiatric disorders. This review synthesizes existing information on the ontogeny of SERT during embryonic and early postnatal development though adolescence, along with factors that influence its expression and function during these critical developmental windows. We integrate this knowledge to emphasize how inappropriate SERT expression or its dysregulation may be linked to the pathophysiology of psychiatric, cardiovascular and gastrointestinal diseases.
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Affiliation(s)
- Lynette C Daws
- Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA.
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Gould GG, Hensler JG, Burke TF, Benno RH, Onaivi ES, Daws LC. Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior. J Neurochem 2011; 116:291-303. [PMID: 21070242 PMCID: PMC3012263 DOI: 10.1111/j.1471-4159.2010.07104.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT(1A) and 5-HT(2A) receptor densities among BTBR and C57 strains. Autoradiographic [(3) H] cyanoimipramine (1 nM) binding to SERT was 20-30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates, [(3) H] citalopram maximal binding (B(max) ) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (K(D) ) was 2.0 ± 0.3 nM versus 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5-HT(1A) and 5-HT(2A) receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [(35) S] GTPγS binding in the BTBR hippocampal CA(1) region was 28% higher, indicating elevated 5-HT(1A) capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT(1A) receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D(2) /5-HT(2) receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying, but failed to improve sociability. Overall, altered SERT and/or 5-HT(1A) functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.
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MESH Headings
- Animals
- Brain/drug effects
- Brain/metabolism
- Brain/physiology
- Buspirone/pharmacology
- Fluoxetine/pharmacology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred Strains
- Protein Binding/physiology
- Protein Transport
- Receptor, Serotonin, 5-HT1A/metabolism
- Receptor, Serotonin, 5-HT1A/physiology
- Receptor, Serotonin, 5-HT2A/metabolism
- Receptor, Serotonin, 5-HT2A/physiology
- Serotonin Plasma Membrane Transport Proteins/metabolism
- Serotonin Plasma Membrane Transport Proteins/physiology
- Social Behavior
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Affiliation(s)
- Georgianna G Gould
- Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
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Silva CMD, Gonçalves L, Manhaes-de-Castro R, Nogueira MI. Postnatal fluoxetine treatment affects the development of serotonergic neurons in rats. Neurosci Lett 2010; 483:179-83. [PMID: 20696211 DOI: 10.1016/j.neulet.2010.08.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Revised: 07/29/2010] [Accepted: 08/01/2010] [Indexed: 11/15/2022]
Abstract
The goal of the present study was to investigate morphological changes in the serotonergic neurons/terminals in the dorsal (DR) and median (MnR) raphe nuclei and on the hippocampal dentate gyrus (DG) in neonatal rats treated from the 1st to the 21st postnatal day with fluoxetine (10 mg/kg sc, daily) or drug vehicle (0.9% saline 1 ml/kg). The results show that postnatal chronic treatment with fluoxetine promoted: (1) a smaller body weight increase during the pre-weaning period; (2) smaller number of 5-HT neurons in the DR; (3) smaller 5-HT neuronal cell bodies (area, perimeter and diameter) in the DR and the MnR and (4) diminished serotonergic terminals in the DG. These data suggest that the development of the serotonergic system was impaired and that early exposure to fluoxetine damaged the morphology of 5-HT neurons in young adult rats. While these findings are consistent with other work, more studies are needed to better clarify the effects of postnatal chronic treatment with fluoxetine on the serotonergic system and, consequently, on the functions modulated by serotonin.
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Affiliation(s)
- Cristiano Mendes da Silva
- Department of Biosciences, Federal University of Sao Paulo/UNIFESP (Campus Baixada Santista), 11060-001 Santos, Brazil.
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Iñiguez SD, Warren BL, Bolaños-Guzmán CA. Short- and long-term functional consequences of fluoxetine exposure during adolescence in male rats. Biol Psychiatry 2010; 67:1057-66. [PMID: 20172503 PMCID: PMC2868075 DOI: 10.1016/j.biopsych.2009.12.033] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 12/18/2009] [Accepted: 12/22/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is prescribed for the treatment of major depressive disorder in young populations. Here, we explore the short- and long-term consequences of adolescent exposure to FLX on behavioral reactivity to emotion-eliciting stimuli. METHODS Adolescent male rats received FLX (10 mg/kg) twice daily for 15 consecutive days (postnatal days 35-49). The influence of FLX on behavioral reactivity to rewarding and aversive stimuli was assessed 24 hours (short-term) or 3 weeks after FLX treatment (long-term). A separate group of adult rats was also treated with FLX (postnatal days 65-79) and responsiveness to forced swimming was assessed at identical time intervals as with the adolescents. RESULTS Fluoxetine exposure during adolescence resulted in long-lasting decreases in behavioral reactivity to forced swimming stress and enhanced sensitivity to sucrose and to anxiety-eliciting situations in adulthood. The FLX-induced anxiety-like behavior was alleviated by re-exposure to FLX in adulthood. Fluoxetine treatment during adolescence also impaired sexual copulatory behaviors in adulthood. Fluoxetine-treated adult rats did not show changes in behavioral reactivity to forced swim stress as observed in those treated during adolescence and tested in adulthood. CONCLUSIONS Treating adolescent rats with FLX results in long-lived complex outputs regulated by the emotional valence of the stimulus, the environment in which it is experienced, and the brain circuitry likely being engaged by it. Our findings highlight the need for further research to improve our understanding of the alterations that psychotropic exposure may induce on the developing nervous system and the potential enduring effects resulting from such treatments.
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Affiliation(s)
- Sergio D Iñiguez
- Department of Psychology, Florida State University, Tallahassee, FL 32306-4301, USA
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Dubovický M. Neurobehavioral manifestations of developmental impairment of the brain. Interdiscip Toxicol 2010; 3:59-67. [PMID: 21217874 PMCID: PMC2984125 DOI: 10.2478/v10102-010-0012-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2010] [Revised: 05/20/2010] [Accepted: 06/03/2010] [Indexed: 01/04/2023] Open
Abstract
Individual characteristics of human nature (e.g. introversion, extroversion, mood, activity, adaptability, aggressiveness, social ability, anxiety) do not need to be primarily innate. They can be determined by the action of various influences and their interactions on functional development of the brain. There is ample epidemiological and experimental evidence that chemical and/or physical factors acting during sensitive time windows of the brain development can cause mental, behavioral, emotional and/or cognitive disorders. Environmental pollutants, addictive substances, drugs, malnutrition, excessive stress and/or hypoxia-ischemia were reported to induce functional maldevelopment of the brain with consequent neurobehavioral disorders. The article provides review on most significant neurobehavioral manifestations of developmental impairment of the brain during prenatal, perinatal and early postnatal period. The most known adverse factors causing developmental neurobehavioral dysfunctions in humans as well as in experimental animals are discussed.
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Affiliation(s)
- Michal Dubovický
- Institute of Experimental Pharmacology & Toxicology, Slovak Academy of Sciences, SK-84104, Bratislava, Slovakia
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Hadjikhani N. Serotonin, pregnancy and increased autism prevalence: Is there a link? Med Hypotheses 2010; 74:880-3. [DOI: 10.1016/j.mehy.2009.11.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Accepted: 11/16/2009] [Indexed: 10/20/2022]
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[SSRIs and pregnancy: a review of the literature]. Encephale 2010; 36:513-6. [PMID: 21130237 DOI: 10.1016/j.encep.2010.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Accepted: 12/30/2009] [Indexed: 11/23/2022]
Abstract
OBJECTIVE A review of the consequences of maternal depression on fetal and infant development and the risk and benefits of SSRI use. METHOD We have reviewed the literature published on PubMed between January 1980 and February 2009 using the following keywords: SSRI, depression, pregnancy, abnormality, teratogenic effect. RESULTS Pregnancies complicated by the onset or recurrence of a major depressive disorder constitute a complex medical situation. The management of such situations is based on the principle of avoiding, as far as possible, the exposure of the developing foetus to both the maternal illness and the potential teratogenic effects of psychotropic drugs. Epidemiological studies show that maternal depression is a very frequent disease: 10 to 16% of pregnant women fulfill major depressive disorder diagnostic criteria and 15% suffer from postpartum depression. The consequences of such exposure on fetal and infant development are so harmful that a pharmacological treatment is highly recommended. Nowadays, the information available on the safety of SSRI use in pregnancy is abundant and these molecules are probably the most studied drugs in pregnant women. Their beneficial effects largely prevail over their potential fetal/neonatal risks and it is unlikely that any marked teratogenic effect occurs, with the possible exception of an increased risk for cardiovascular defects after maternal use of paroxetine. However, transient neonatal symptoms are common after SSRI use in late pregnancy. These include transient autonomic, gastrointestinal, somatic, and clinical respiratory manifestations in the immediate neonatal period. CONCLUSION Treatment of maternal depression during pregnancy and immediate neonatal period is uniformly recommended despite the potential side effects on the fetus and newborn. With a possible exception for paroxetine, maternal treatment with SSRIs during pregnancy is not associated with significantly increased risks of congenital defects.
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Zafeiriou DI, Ververi A, Vargiami E. The serotonergic system: its role in pathogenesis and early developmental treatment of autism. Curr Neuropharmacol 2010; 7:150-7. [PMID: 19949574 PMCID: PMC2730007 DOI: 10.2174/157015909788848848] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Revised: 01/15/2009] [Accepted: 03/27/2009] [Indexed: 11/22/2022] Open
Abstract
Autism is a severe childhood disorder already presenting in the first 3 years of life and, therefore, strongly correlated with neurodevelopmental alterations in prenatal, as well as postnatal period. Neurotransmitters hold a pivotal role in development by providing the stimulation needed for synapses and neuronal networks to be formed during the critical period of neuroplasticity. Aberrations of the serotonergic system modify key processes in the developing brain and are strongly implicated in the pathophysiology of developmental disorders. Evidence for the role of serotonin in autism emerges from neuropathological, imaging and genetic studies. Due to its developmental arrest, autism requires early intervention that would, among others, target the disrupted serotonergic system and utilize brain plasticity to elicit clinically important brain changes in children.
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Affiliation(s)
- D I Zafeiriou
- 1st Department of Pediatrics, Aristotle University of Thessaloniki, Greece.
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Gestational exposure to the organophosphate chlorpyrifos alters social-emotional behaviour and impairs responsiveness to the serotonin transporter inhibitor fluvoxamine in mice. Psychopharmacology (Berl) 2010; 208:99-107. [PMID: 19921154 DOI: 10.1007/s00213-009-1713-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Accepted: 10/23/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND The organophosphate chlorpyrifos (CPF) is a pesticide largely used worldwide. Studies from animal models indicate that CPF exposure during development at low doses can target different neurotransmitter systems in the absence of overt cholinergic effects. METHODS Late gestational exposure (gestational days 14-17) to CPF at the dose of 6 mg/kg was evaluated in CD-1 mice at adulthood. Neurobehavioural effects likely involving serotonin (5-hydroxytryptamine, 5HT) transmission were assessed both in males and females, through the light-dark exploration test to assess CPF effects on anxiety profiles and the forced swimming test to evaluate the response to the 5HT transporter (5HTT) inhibitor fluvoxamine (30 mg/kg). In females only, we evaluated the effects of gestational exposure to CPF on maternal aggression, under basal condition or after injection of fluvoxamine. RESULTS Gestational CPF exposure increased anxiety levels only in female mice, as shown by the augmented thigmotaxis behaviour and the lower latency to enter in the dark compartment. In the forced swimming test, no differences between CPF and control mice were found when assessed under basal condition (saline administration), but both male and female CPF mice missed to show the typical behavioural effects of the 5HTT inhibitor fluvoxamine. During maternal aggression, CPF females showed lower propensity to and intensity of aggressive behaviour, together with mild decreased responsiveness to fluvoxamine administration. CONCLUSIONS Overall, the present results confirm a specific and sex-dependent vulnerability of affective/emotional domains to developmental CPF exposure. Furthermore, data provide clear indication on the disrupting effects of prenatal CPF on serotoninergic transmission.
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Safety of SSRIs in Pregnancy. Obstet Gynecol 2009. [DOI: 10.1097/01.aog.0000347992.68280.b8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Neonatal fluoxetine exposure affects the neuronal structure in the somatosensory cortex and somatosensory-related behaviors in adolescent rats. Neurotox Res 2009; 15:212-23. [PMID: 19384594 DOI: 10.1007/s12640-009-9022-4] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Revised: 10/29/2008] [Accepted: 12/12/2008] [Indexed: 10/20/2022]
Abstract
Selective serotonin reuptake inhibitor (SSRI)-type antidepressants are often prescribed to depressive pregnant women for their less adverse side effects. However, growing evidences have shown increased congenital malformations and poor neonatal adaptation in the perinatal SSRI-exposed human infants as well as animal pups. In this study, we examined the effects of early exposure of fluoxetine, the most popular SSRI-type antidepressant, on the developing somatosensory system. Physiological saline or fluoxetine (10 mg/kg) was subcutaneously injected into neonatal rats from P0 to P6. Somatosensory-related behaviors were examined in adolescence (P30-P35). Morphological features of the primary somatosensory cortex were checked at P7 and P35. The tactile and thermal perceptions as well as locomotor activity were affected by neonatal fluoxetine treatment. At the morphological level, the number of branch tips of thalamocortical afferents to the somatosensory cortex was reduced in the fluoxetine-treated rats. Furthermore, the spiny stellate neurons in the layer IV somatosensory cortex had reduced dendritic span and complexity with fewer branches, shorter dendritic length, and smaller dendritic field. The spine density of spiny stellate neurons was significantly reduced whereas the spine length of mushroom- and branched-type was increased. Taken together, these results indicate that neonatal fluoxetine administration has long-lasting effects on the function and structure in the somatosensory system. Sensory information processing may be disturbed in the neonatal fluoxetine-treated animals due to the structural deformation in the thalamocortical afferents and dendritic structures of the spiny stellate neurons in the layer IV somatosensory cortex.
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