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1.
Proc Natl Acad Sci U S A ; 109(14): 5469-74, 2012 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-22431635

RESUMEN

Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.


Asunto(s)
Trastorno Autístico/genética , Receptores de Serotonina/fisiología , Serotonina/sangre , Conducta Social , Conducta Estereotipada , Animales , Trastorno Autístico/sangre , Trastorno Autístico/fisiopatología , Modelos Animales de Enfermedad , Homeostasis , Ratones
2.
J Med Primatol ; 43(4): 284-287, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25431504

RESUMEN

We studied development of the fetal serotonergic central nervous system in a baboon, non-human primate model of intrauterine growth restriction (IUGR). Fetal (90% of full-term) IUGR brains were comparable in size to controls, but have reduced expression of serotonergic proteins and mRNAs, as well as having fewer serotonergic neurons.

3.
Proc Natl Acad Sci U S A ; 108(9): 3785-90, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21282638

RESUMEN

Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (i.e., "ecstasy"), also impact 5-HT signaling. To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT, slc6a4) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autoreceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants.


Asunto(s)
Antidepresivos/farmacología , Cocaína/farmacología , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Técnicas de Sustitución del Gen , Técnicas In Vitro , Cinética , Ratones , Ratones Transgénicos , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/metabolismo , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo
4.
Behav Brain Res ; 349: 116-124, 2018 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-29660440

RESUMEN

Maternal nutrition impacts fetal development, and may play a role in determining resilience to stress and vulnerability to stress-precipitated psychiatric disorders, such as anxiety and depression. In this study, we examined the effect of a reduction in maternal dietary protein during pregnancy on the brain neurochemistry and behavior of offspring. We focused specifically on the serotonin system, the 5-HT1A receptor and the responsivity of offspring as adults to stress. Dams were fed either a low protein diet (10% protein by weight) or isocaloric control diet (20% protein by weight). The low protein diet did not alter maternal food intake and body weight, or litter size and the average birth weight of male or female littermates. 5-HT1A receptor function, as measured by quantitative autoradiography of 8-OH-DPAT (1 µM)-stimulated [35S]GTPγS binding, was markedly reduced in hippocampus of weanling female, but not male offspring (postnatal day, PND 21) of dams fed the low protein diet. The number of serotonergic cell bodies in the rostral raphe, and 5-HT metabolism in the limbic system of weanling offspring was not altered by maternal low protein diet. The deficit in hippocampal 5-HT1A receptor function observed in weanling female offspring persisted into adulthood (PND 112), and was accompanied by an increased sensitivity to stress, specifically increased immobility during a 15-minute forced swim challenge and increased anorexia following 30-minute restraint (PND 97-100). The present work begins to uncover important future directions for understanding the early developmental origins of resilience to stress, and factors that may put individuals at greater risk for stress-related psychiatric disorders.


Asunto(s)
Complicaciones del Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal , Deficiencia de Proteína , Receptor de Serotonina 5-HT1A/metabolismo , Resiliencia Psicológica , Estrés Psicológico , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Femenino , Masculino , Embarazo , Distribución Aleatoria , Ratas Wistar , Caracteres Sexuales
5.
ACS Chem Neurosci ; 8(5): 1011-1018, 2017 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-27959497

RESUMEN

Previous studies of transgenic mice carrying a single isoleucine to methionine substitution (I172M) in the serotonin transporter (SERT) demonstrated a loss of sensitivity to multiple antidepressants (ADs) at SERT. However, the ability of AD metabolites to antagonize SERT was not assessed. Here, we evaluated the selectivity and potency of these metabolites for inhibition of SERT in mouse brain-derived synaptosomes and blood platelets from wild-type (I172 mSERT) and the antidepressant-insensitive mouse M172 mSERT. The metabolites norfluoxetine and desmethylsertraline lost the selectivity demonstrated by the parent compounds for inhibition of wild-type mSERT over M172 mSERT, whereas desvenlafaxine and desmethylcitalopram retained selectivity. Furthermore, we show that the metabolite desmethylcitalopram accumulates in the brain and that the metabolites desmethylcitalopram, norfluoxetine, and desvenlafaxine inhibit serotonin uptake in wild-type mSERT at potencies similar to those of their parent compounds, suggesting that metabolites may play a role in effects observed following AD administration in wild-type and M172 mice.


Asunto(s)
Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sinaptosomas/efectos de los fármacos , Animales , Citalopram/análogos & derivados , Citalopram/farmacología , Fluoxetina/análogos & derivados , Fluoxetina/farmacología , Ratones , Sertralina/análogos & derivados , Sertralina/farmacología , Sinaptosomas/metabolismo
6.
Ital J Anat Embryol ; 120(3): 162-71, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-27086415

RESUMEN

Cadaver dissection remains a cornerstone in the study of anatomical sciences by medical students. However, this activity can cause emotions that may affect learning outcomes. This study, which involved medical students of various cultural backgrounds, assessed their responses to dissection. Medicine I year students (n = 100) at Oakland University William Beaumont School of Medicine were invited to complete a questionnaire after the first week of dissection, and again at the end of the course. The questionnaire asked for demographics, and assessed the students' appraisal of their dissection experience, cultural influences, coping activities and learning outcomes. After the first week of dissection, most of the students found the experience challenging, stimulating, exciting and informative, rather than nauseating or unbearable. Still, some students found the experience anxiety-provoking, especially when they thought about human mortality. Cultural background influenced the students' emotional development as they worked through the course. Most of the participants agreed that dissection promotes teamwork, familiarity with the human body, and integration of the theoretical knowledge with practical application. At the end of the course, dissection was significantly less anxiety-provoking, and, interestingly, the study found that culture and religious beliefs became more important to the students. Most students agreed that dissection is important, relevant, and necessary, and has the potential to improve learning outcomes that are essential to the development of physicians. The study suggests that an introductory course in social, behavioral and ethical considerations be presented at the beginning of the medical curriculum.


Asunto(s)
Cadáver , Disección/psicología , Estudiantes de Medicina/psicología , Adaptación Psicológica , Cultura , Femenino , Humanos , Masculino , Estudiantes de Medicina/estadística & datos numéricos , Adulto Joven
7.
J Neurodev Disord ; 1(2): 158-71, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19960097

RESUMEN

Alterations in peripheral and central indices of serotonin (5-hydroxytryptamine, 5-HT) production, storage and signaling have long been associated with autism. The 5-HT transporter gene (HTT, SERT, SLC6A4) has received considerable attention as a potential risk locus for autism-spectrum disorders, as well as disorders with overlapping symptoms, including obsessive-compulsive disorder (OCD). Here, we review our efforts to characterize rare, nonsynonymous polymorphisms in SERT derived from multiplex pedigrees carrying diagnoses of autism and OCD and present the initial stages of our effort to model one of these variants, Gly56Ala, in vivo. We generated a targeting vector to produce the Gly56Ala substitution in the Slc6a4 locus by homologous recombination. Following removal of a neomycin resistance selection cassette, animals exhibiting germline transmission of the Ala56 variant were bred to establish a breeding colony on a 129S6 background, suitable for initial evaluation of biochemical, physiological and behavioral alterations relative to SERT Gly56 (wild-type) animals. SERT Ala56 mice were achieved and exhibit a normal pattern of transmission. The initial growth and gross morphology of these animals is comparable to wildtype littermate controls. The SERT Ala56 variant can be propagated in 129S6 mice without apparent disruption of fertility and growth. We discuss both the opportunities and challenges that await the physiological/behavioral analysis of Gly56Ala transgenic mice, with particular reference to modeling autism-associated traits.

8.
Dig Dis Sci ; 53(1): 229-41, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17530400

RESUMEN

Calcitonin gene-related peptide (CGRP) is thought to be involved in the regulation of gastric and mesenteric blood flow, in the control of gastric acid secretion and in the modulation of intestinal motility, yet the precise physiological roles of CGRP remain to be elucidated. To further examine the role(s) of CGRP in gastrointestinal function, we examined mutant mice lacking alphaCGRP or betaCGRP expression. Mutant mice did not demonstrate any overt phenotypic changes, yet exhibited a spontaneous, adult-onset colitis and increased colonic damage using a dextran sulfate sodium model of experimental colitis. Surprisingly, mice lacking betaCGRP show no obvious alterations in CGRP immunoreactivity in the gut, accompanied by an increase in alphaCGRP messenger RNA expression, suggesting an adaptive mechanism to compensate for the lack of betaCGRP. These data demonstrate that both alphaCGRP and betaCGRP play a protective role in the generation of spontaneous colitis, supporting a role for both extrinsic and intrinsic CGRP-containing neurons.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/genética , Colitis/metabolismo , Expresión Génica , ARN/genética , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Colitis/inducido químicamente , Colitis/genética , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunohistoquímica , Ratones , Ratones Mutantes , Reacción en Cadena de la Polimerasa , Índice de Severidad de la Enfermedad
9.
Am J Health Syst Pharm ; 65(21): e53-71, 2008 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-18945847

RESUMEN

PURPOSE: Current hospital and health-system participation in and the future capacity for experiential education for pharmacy students was investigated. METHODS: An online survey of ASHP members identified as U.S. pharmacy directors was conducted to assess their current and future involvement in partnering with colleges and schools to meet the experiential education requirements for doctor of pharmacy students and the current status of the student learning experiences. Questionnaire items examined the factors on which expanded involvement in experiential education would depend, the nature of support provided by colleges and schools, the types of experiences available for students, respondents' perceptions of factors influencing the quality of experiential education, the value of experiential education to the sites, respondents' challenges and concerns about experiential education, and respondents' current capacity and projections for introductory and advanced experiences through 2012. RESULTS: Data from 549 respondents were analyzed. Most respondents indicated that they had conducted advanced experiences for their 2007 graduates and anticipated that they would continue to do so. Among the top challenges identified regarding advanced experiences were concerns about time to serve and be trained as preceptors and a lack of standardization and coordination among colleges and schools. Hospitals forecasting their future capacity to accommodate students indicated that their projections were highly dependent on the number of pharmacists at their hospitals. Many respondents noted that their capacity projections were tied to their ability to expand clinical services at their hospitals. CONCLUSION: A survey of pharmacy directors suggested an ability of U.S. hospitals to conduct advanced experiential education opportunities for pharmacy students through 2012 and to expand introductory experiences.


Asunto(s)
Conducta Cooperativa , Educación en Farmacia/normas , Escolaridad , Hospitales de Enseñanza/normas , Estudiantes de Farmacia , Recolección de Datos/métodos , Recolección de Datos/normas , Recolección de Datos/tendencias , Educación en Farmacia/métodos , Educación en Farmacia/tendencias , Hospitales de Enseñanza/métodos , Hospitales de Enseñanza/tendencias , Humanos , Servicio de Farmacia en Hospital/métodos , Servicio de Farmacia en Hospital/normas , Servicio de Farmacia en Hospital/tendencias , Preceptoría/métodos , Preceptoría/normas , Preceptoría/tendencias , Estados Unidos
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