RESUMEN
BACKGROUND AND PURPOSE: Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene. Our hypothesis was that regional analysis of cortical brain degeneration may identify brain regions that are affected earliest and most severely by the disease. MATERIALS AND METHODS: Fifty-two high-resolution 3T MR imaging datasets were prospectively acquired on 38 subjects with CLN2. A retrospective cohort of 52 disease-free children served as a control population. The FreeSurfer software suite was used for calculation of cortical thickness. RESULTS: An increased rate of global cortical thinning in CLN2 versus control subjects was the primary finding in this study. Three distinct patterns were observed across brain regions. In the first, subjects with CLN2 exhibited differing rates of cortical thinning versus age. This was true in 22 and 26 of 34 regions in the left and right hemispheres, respectively, and was also clearly discernable when considering brain lobes as a whole and Brodmann regions. The second pattern exhibited a difference in thickness from healthy controls but with no discernable change with age (9 left hemispheres, 5 right hemispheres). In the third pattern, there was no difference in either the rate of cortical thinning or the mean cortical thickness between groups (3 left hemispheres, 3 right hemispheres). CONCLUSIONS: This study demonstrates that CLN2 causes differential rates of degeneration across the brain. Anatomic and functional regions that degenerate sooner and more severely than others compared with those in healthy controls may offer targets for directed therapies. The information gained may also provide neurobiologic insights regarding the mechanisms underlying disease progression.
Asunto(s)
Encéfalo/patología , Degeneración Nerviosa/patología , Lipofuscinosis Ceroideas Neuronales/patología , Niño , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Tripeptidil Peptidasa 1RESUMEN
BACKGROUND AND PURPOSE: LINCL is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene that encodes for tripeptidyl peptidase 1, a lysosomal enzyme necessary for the degradation of products of cellular metabolism. With the goal of developing quantitative noninvasive imaging biomarkers sensitive to disease progression, we evaluated a 5-component MR imaging metric and tested its correlation with a clinically derived disease-severity score. MATERIALS AND METHODS: MR imaging parameters were measured across the brain, including quantitative measures of the ADC, FA, nuclear spin-spin relaxation times (T2), volume percentage of CSF (%CSF), and NAA/Cr ratios. Thirty MR imaging datasets were prospectively acquired from 23 subjects with LINCL (2.5-8.4 years of age; 8 male/15 female). Whole-brain histograms were created, and the mode and mean values of the histograms were used to characterize disease severity. RESULTS: Correlation of single MR imaging parameters against the clinical disease-severity scale yielded linear regressions with R2 ranging from 0.25 to 0.70. Combinations of the 5 biomarkers were evaluated by using PCA. The best combination included ADC, %CSF, and NAA/Cr (R2=0.76, P<.001). CONCLUSIONS: The multiparametric disease-severity score obtained from the combination of ADC, %CSF, and NAA/Cr whole-brain MR imaging techniques provided a robust measure of disease severity, which may be useful in clinical therapeutic trials of LINCL in which an objective assessment of therapeutic response is desired.
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Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Lipofuscinosis Ceroideas Neuronales/patología , Índice de Severidad de la Enfermedad , Factores de Edad , Aminopeptidasas/genética , Artefactos , Biomarcadores/metabolismo , Encéfalo/metabolismo , Niño , Preescolar , Bases de Datos Factuales , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Lipofuscinosis Ceroideas Neuronales/genética , Serina Proteasas/genética , Tripeptidil Peptidasa 1RESUMEN
BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (LINCL) is associated with progressive degeneration of the brain and retina starting in early childhood. METHODS: Thirty-two individual neurologic, ophthalmologic, and CNS imaging (MRI and MRS) assessments of 18 children with LINCL were analyzed. Disease severity was followed by two rating scales, one previously established but modified to solely assess the brain and exclude the retinal disease (modified Hamburg LINCL scale), and a newly developed scale, with expanded evaluation of the CNS impairment (Weill Cornell LINCL scale). RESULTS: For the 18 children, the Weill Cornell scale yielded a closer correlation with both age and time since initial clinical manifestation of the disease than did the modified Hamburg scale. There were no significant differences as a function of age or time since initial manifestation of the disease in the rating scales among the most frequent CLN2 mutations (G3556C, 56% of all alleles or C3670T, 22% of all alleles). Measurements of cortical MRS N-acetyl-aspartate content, MRI ventricular, gray matter and white matter volume, and cortical apparent diffusion coefficient correlated to a variable degree with the age of the children and the time since initial clinical manifestation of the disease. All imaging measurements correlated better with the Weill Cornell CNS scale compared to the modified Hamburg LINCL scale. CONCLUSION: The data suggest that the Weill Cornell late infantile neuronal ceroid lipofuscinosis (LINCL) scale, together with several of the MRI measurements, may be useful in the assessment of severity and progression of LINCL and for the evaluation of novel therapeutic strategies.
Asunto(s)
Lipofuscinosis Ceroideas Neuronales/fisiopatología , Índice de Severidad de la Enfermedad , Adolescente , Factores de Edad , Edad de Inicio , Aminopeptidasas , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análisis , Corteza Cerebral/química , Corteza Cerebral/patología , Niño , Preescolar , Análisis Mutacional de ADN , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Progresión de la Enfermedad , Endopeptidasas/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación Missense , Examen Neurológico , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , Resonancia Magnética Nuclear Biomolecular , Oftalmoscopía , Tamaño de los Órganos , Mutación Puntual , Retina/patología , Serina Proteasas , Hermanos , Tripeptidil Peptidasa 1RESUMEN
BACKGROUND AND PURPOSE: Late infantile neuronal ceroid lipofuscinosis (LINCL), a form of Batten disease, is a fatal neurodegenerative genetic disorder, diagnosed via DNA testing, that affects approximately 200 children in the United States at any one time. This study was conducted to evaluate whether quantitative data derived by diffusion-weighted MR imaging (DWI) techniques can supplement clinical disability scale information to provide a quantitative estimate of neurodegeneration, as well as disease progression and severity. MATERIALS AND METHODS: This study prospectively analyzed 32 DWI examinations from 18 patients having confirmed LINCL at various stages of disease. A whole-brain apparent diffusion coefficient (ADC) histogram was fitted with a dual Gaussian function combined with a function designed to model voxels containing a partial volume fraction of brain parenchyma versus CSF. Previously published whole-brain ADC values of age-matched control subjects were compared with those of the LINCL patients. Correlations were tested between the peak ADC of the fitted histogram and patient age, disease severity, and a CNS disability scale adapted for LINCL. RESULTS: ADC values assigned to brain parenchyma were higher than published ADC values for age-matched control subjects. ADC values between patients and control subjects began to differ at 5 years of age based on 95% confidence intervals. ADC values had a nearly equal correlation with patient age (R2=0.71) and disease duration (R2=0.68), whereas the correlation with the central nervous system disability scale (R2=0.27) was much weaker. CONCLUSION: This study indicates that brain ADC values acquired using DWI may be used as an independent measure of disease severity and duration in LINCL.
Asunto(s)
Encéfalo/patología , Imagen de Difusión por Resonancia Magnética/métodos , Interpretación de Imagen Asistida por Computador/métodos , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Índice de Severidad de la Enfermedad , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Lipofuscinosis Ceroideas Neuronales/clasificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Morphometric cerebral characteristics were studied in children with prenatal poly-substance exposure (n=14) compared to controls (n=14) without such exposure. Ten of the substance-exposed children were born to mothers who used opiates (heroin) throughout the pregnancy. Groups were compared across 16 brain measures: cortical gray matter, cerebral white matter, hippocampus, amygdala, thalamus, accumbens area, caudate, putamen, pallidum, brainstem, cerebellar cortex, cerebellar white matter, lateral ventricles, inferior lateral ventricles, and the 3rd and 4th ventricles. In addition, continuous measurement of thickness across the entire cortical mantle was performed. Volumetric characteristics were correlated with ability and questionnaire assessments 2 years prior to scan. Compared to controls, the substance-exposed children had smaller intracranial and brain volumes, including smaller cerebral cortex, amygdala, accumbens area, putamen, pallidum, brainstem, cerebellar cortex, cerebellar white matter, and inferior lateral ventricles, and thinner cortex of the right anterior cingulate and lateral orbitofrontal cortex. Pallidum and putamen appeared especially reduced in the subgroup exposed to opiates. Only volumes of the right anterior cingulate, the right lateral orbitofrontal cortex and the accumbens area, showed some association with ability and questionnaire measures. The sample studied is rare and hence small, so conclusions cannot be drawn with certainty. Morphometric group differences were observed, but associations with previous behavioral assessment were generally weak. Some of the volumetric differences, particularly thinner cortex in part of the right lateral orbitofrontal cortex, may be moderately involved in cognitive and behavioral difficulties more frequently experienced by opiate and poly-substance-exposed children.
Asunto(s)
Encéfalo/efectos de los fármacos , Discapacidades del Desarrollo/inducido químicamente , Heroína/toxicidad , Drogas Ilícitas/toxicidad , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Discapacidades para el Aprendizaje/inducido químicamente , Imagen por Resonancia Magnética , Narcóticos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/patología , Encéfalo/patología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Niño , Trastornos de la Conducta Infantil/inducido químicamente , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/patología , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/patología , Dominancia Cerebral/fisiología , Femenino , Estudios de Seguimiento , Humanos , Inteligencia/efectos de los fármacos , Control Interno-Externo , Discapacidades para el Aprendizaje/diagnóstico , Masculino , Pruebas Neuropsicológicas , Embarazo , Valores de Referencia , Ajuste Social , Estadística como Asunto , Escalas de WechslerRESUMEN
Dopamine D(2) long (D(2)L) and D(2) short (D(2)S) isoforms of the D(2) receptor play an important role in psychostimulant-induced neuronal adaptations. In this study, we used quantitative real-time PCR to specifically amplify these two splice variants to examine their mRNA expression in the dorsal striatum (dStr), nucleus accumbens (NAc) and the ventral tegmental area (VTA) of amphetamine-sensitized C57BL/6 mice. We found a significant increase in D(2)L mRNA in the VTA and dStr of amphetamine-treated mice that positively correlated with the sensitized locomotor response. We also found a significant increase in D(2)S mRNA in the VTA. We further examined the role of the Ca(v)1.3 subtype of L-type Ca(2+) channels in up-regulation of D(2)L and D(2)S mRNA in the VTA. Amphetamine-pretreated Ca(v)1.3 wild-type (Ca(v)1.3(+/+)) mice exhibited sensitized behavior and a significant increase in D(2)L and D(2)S mRNA compared with saline-pretreated mice Amphetamine-pretreated homozygous Ca(v)1.3 knockout (Ca(v)1.3(-/-)) mice did not exhibit sensitized behavior. There was a significant increase in D(2)S mRNA, but not D(2)L mRNA. In conclusion, our results find that amphetamine increases D(2)L mRNA expression in the dStr and the VTA, an adaptation that correlates with expression of sensitized behavior and dependence on Ca(v)1.3 Ca(2+) channels.
Asunto(s)
Anfetamina/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Neostriado/efectos de los fármacos , Receptores de Dopamina D2/genética , Área Tegmental Ventral/efectos de los fármacos , Trastornos Relacionados con Anfetaminas/genética , Trastornos Relacionados con Anfetaminas/metabolismo , Trastornos Relacionados con Anfetaminas/fisiopatología , Animales , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Neostriado/metabolismo , Neostriado/fisiopatología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiopatologíaRESUMEN
Methylphenidate (MPH), a dopamine reuptake inhibitor, is used increasingly to treat attention deficit and hyperactivity disorders in children. Given that dopaminergic mechanisms, contribute to the structural and functional maturation of brain circuitry, consideration of the potential influence of MPH in disrupting such processes seems warranted. Following a similar logic regarding the relevance of glutamate neurotransmission in mediating aspects of brain maturation, we and others have previously utilized in vivo and in vitro studies of the developing rodent brain to establish that MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist has both neuroprotective and pro-apoptotic actions. In this study we used a neonatal murine model of excitotoxin-induced cortical injury to compare such actions between MPH and MK-801, and found that MPH shared some biological properties with MK-801. Specifically, both drugs were neuroprotective against excitotoxic challenge resulting in neonatal brain lesions and in vitro neuronal death, but both drugs also exacerbated programmed neural cell death. However, this profile of action was not shared by the dopamine reuptake blocker GBR-12783, a molecule which like MPH binds to and blocks the dopamine transporter, but which is structurally dissimilar to MPH, suggesting that inhibition of dopamine reuptake alone cannot explain the results from our MPH studies. The implications of our findings are that when studied in our developmental mouse model both drugs demonstrate similar capacities to be either neuroprotective or pro-apoptotic, depending on the specific biologic setting in which they act. Additional studies to identify some potential positive as well as negative consequences of exposure to these drugs during brain development in clinical settings are warranted.
Asunto(s)
Encéfalo/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Metilfenidato/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Encéfalo/embriología , Lesiones Encefálicas/inducido químicamente , Inhibidores de Captación de Dopamina/farmacología , Ácido Iboténico/toxicidad , Etiquetado Corte-Fin in Situ , Ratones , Neuronas/patología , Piperazinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms. Endogenous NT-3 expression, strikingly absent in noradrenergic neurons of postnatal and adult brain, is present in afferent sources of the dorsal medulla and is upregulated after chronic morphine exposure in noradrenergic projection areas of the ventral forebrain. NT-3 expressed by non-catecholaminergic neurons may modulate opiate withdrawal and noradrenergic signalling.
Asunto(s)
Encéfalo/fisiología , Dependencia de Morfina/genética , Proteínas del Tejido Nervioso , Neuronas/fisiología , Neurotrofina 3/fisiología , Síndrome de Abstinencia a Sustancias/genética , Tirosina 3-Monooxigenasa/genética , Envejecimiento , Animales , Reacción de Prevención/fisiología , Encéfalo/crecimiento & desarrollo , Colforsina/farmacología , AMP Cíclico/fisiología , Estimulación Eléctrica , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Regulación Enzimológica de la Expresión Génica , Técnicas In Vitro , Proteínas de Filamentos Intermediarios/genética , Locus Coeruleus/enzimología , Locus Coeruleus/fisiología , Ratones , Ratones Noqueados , Ratones Transgénicos , Morfina/farmacología , Dependencia de Morfina/fisiopatología , Nestina , Neuronas/efectos de los fármacos , Neurotrofina 3/deficiencia , Neurotrofina 3/genética , Transducción de Señal/fisiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Tirosina 3-Monooxigenasa/metabolismoAsunto(s)
Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/complicaciones , Cocaína/toxicidad , Inhibidores de Captación de Dopamina/toxicidad , Malformaciones del Sistema Nervioso/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Animales , Encéfalo/anomalías , Encéfalo/patología , Trastornos Relacionados con Cocaína/patología , Trastornos Relacionados con Cocaína/terapia , Modelos Animales de Enfermedad , Femenino , Humanos , Malformaciones del Sistema Nervioso/patología , Embarazo , Centros de Tratamiento de Abuso de SustanciasRESUMEN
Functional MRI of rat brain was performed at 2 Tesla following intravenous injection of cocaine in order to 1) determine if changes in CBV and changes in BOLD signal were regionally coupled in brain parenchyma, and 2) compare the sensitivities of these imaging methods across different brain structures. Percent changes in CBV and BOLD relaxation rate were spatially and temporally coupled during this graded brain activation. The use of contrast agent increased functional sensitivity in all parenchymal brain structures, with a strong but predictable dependence on the resting-state blood volume fraction. Magn Reson Med 45:443-447, 2001.
Asunto(s)
Encéfalo/irrigación sanguínea , Cocaína/farmacología , Aumento de la Imagen , Imagen por Resonancia Magnética/métodos , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Velocidad del Flujo Sanguíneo/fisiología , Volumen Sanguíneo/efectos de los fármacos , Volumen Sanguíneo/fisiología , Encéfalo/patología , Mapeo Encefálico , Medios de Contraste , Óxido Ferrosoférrico , Interpretación de Imagen Asistida por Computador , Hierro , Masculino , Óxidos , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiologíaRESUMEN
The neurotoxic consequences of intrauterine exposure to drugs of abuse, including cocaine, may include compromised fetal brain development with associated lasting behavioral alterations. Some infants exposed to cocaine in utero demonstrate impairments in reactivity and altered behavioral responses to stressful conditions. Alterations in arousal regulation can impact on socialization, adaptation, and educability. Moreover, such alterations may render cocaine-exposed children more vulnerable to the adverse developmental impact of stressful situations, with implications for subsequent behavior and psychopathology. Animal models facilitate the independent analysis and identification of genetic, intrauterine, and postnatal environmental factors in contributing to cocaine-induced alterations in behavioral and neurochemical responses to stressors. Utilizing a prenatal mouse model of gestational cocaine exposure we have identified a behavioral alteration evident as decreased duration of footshock-induced immobility termed "freezing" in cocaine-exposed adults as compared with controls. However, this attenuated behavioral response was not accompanied by demonstrable alterations in corticosterone response, nor was the corticosterone response altered in cocaine-exposed adults following a more protracted restraint-induced stress. The dissociation of these behavioral and neurochemical indices of altered response to stressors may provide insights regarding brain mechanisms underlying alterations in behavioral reactivity to stressful conditions following in utero cocaine exposure. In addition, this preclinical study may have implications for improved diagnostics and therapeutics for infants and children exposed to cocaine in the womb.
RESUMEN
In this article, the authors provide a conceptual framework in which to consider alternative approaches to identify the developmental consequences of exposing the developing brain to neurotoxic substances. Concepts underlying brain development and issues regarding neurobehavioral testing in children are reviewed. In addition, the authors selectively review preclinical data identifying mechanisms contributing to neurobehavioral compromise, and clinical data identifying deficits resulting from exposure to two classes of neurotoxins: exposure to drugs of abuse, including alcohol, nicotine, and cocaine; and exposure to environmental agents, including lead, methyl-mercury, PCBs, and organophosphorus compounds.
Asunto(s)
Discapacidades del Desarrollo/inducido químicamente , Síndromes de Neurotoxicidad/etiología , Neurotoxinas/efectos adversos , Encéfalo/efectos de los fármacos , Niño , Preescolar , Discapacidades del Desarrollo/clasificación , Discapacidades del Desarrollo/diagnóstico , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Síndromes de Neurotoxicidad/clasificación , Síndromes de Neurotoxicidad/diagnóstico , Neurotoxinas/clasificación , Embarazo , Efectos Tardíos de la Exposición PrenatalRESUMEN
We applied a sensitive new functional magnetic resonance imaging technique to identify the pattern and determinants of cocaine-induced brain activation in drug-naive rats. At doses greater than 0.1 mg/kg iv, cocaine produced robust activation throughout cortex with the largest magnitude increase in frontal neocortex. Additionally, we detected selective activation within dopamine-innervated subcortical regions including dorsomedial and ventrolateral striatum, nucleus accumbens region, and dorsal thalamus. Although dose response was similar among activated regions, temporal response differentiated regions along distinct anatomical boundaries with basal ganglia and limbic cortical structures, reaching maximum activation later than frontal neocortex. Pharmacological specificity was demonstrated by blocking cocaine-induced activation with SCH-23390, a selective D1 antagonist. Our data demonstrate the utility of fMRI to identify spatiotemporal patterns of cocaine-induced brain activation and implicate D1 dopaminergic mechanisms in acute cocaine action.
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Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Cocaína/farmacología , Dopamina/fisiología , Transmisión Sináptica/fisiología , Animales , Benzazepinas/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Inyecciones Intravenosas , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inhibidores , Factores de TiempoRESUMEN
Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One locus for autosomal dominant CCM ( CCM1 ) maps to chromosome 7q21-q22. Recombination events in linked family members define a critical region of approximately 2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angiogenesis and cerebrovascular disease.
Asunto(s)
Vasos Sanguíneos/anomalías , Encéfalo/irrigación sanguínea , Proteínas Asociadas a Microtúbulos , Mutación , Proteínas Proto-Oncogénicas/genética , Etnicidad , Ligamiento Genético , Humanos , Proteína KRIT1 , Datos de Secuencia Molecular , Mapeo Físico de CromosomaRESUMEN
The consequences of public health of the acquisition and use of drugs of abuse have been well demonstrated. Despite intense effort, however, progress has been slow in recent years in ascertaining the specific neurodevelopmental effects of these drugs on the children of drug-abusing mothers. The use of animal models allows the investigator to determine the specific biological contributions of prenatal exposure to drugs of abuse on neurodevelopmental outcome while controlling for covariates that have confounded clinical studies, such as altered nutrition in pregnancy, suboptimal rearing environment of the young, and availability of drug and nondrug stimulation to the offspring. This article selectively reviews the preclinical literature on the gestational effects of drugs of abuse with particular emphasis on cocaine, ethanol, and the opiate narcotics. Mechanisms of drug action on the mature and developing brain are summarized. A model of developmental impact on the brain regions underlying drug-induced reward and reinforcement and its potential postnatal importance is presented.
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Feto/efectos de los fármacos , Drogas Ilícitas/efectos adversos , Alcoholismo , Animales , Encéfalo/efectos de los fármacos , Niño , Desarrollo Infantil , Crianza del Niño , Cocaína/efectos adversos , Trastornos Relacionados con Cocaína , Factores de Confusión Epidemiológicos , Modelos Animales de Enfermedad , Etanol/efectos adversos , Femenino , Humanos , Narcóticos/efectos adversos , Fenómenos Fisiológicos de la Nutrición , Trastornos Relacionados con Opioides , Embarazo , Complicaciones del Embarazo , Resultado del Embarazo , Efectos Tardíos de la Exposición Prenatal , Refuerzo en Psicología , Recompensa , Trastornos Relacionados con SustanciasAsunto(s)
Daño Encefálico Crónico/diagnóstico , Trastornos del Espectro Alcohólico Fetal/diagnóstico , Daño Encefálico Crónico/inducido químicamente , Cocaína/efectos adversos , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Recién Nacido , Inteligencia/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Pruebas Neuropsicológicas , Bifenilos Policlorados/efectos adversos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Tiempo de Reacción/efectos de los fármacosRESUMEN
To characterize the effects of cocaine on developing brain we have developed a mouse model of gestational cocaine exposure. We studied pregnant dams injected twice daily with cocaine HCl at 40, 20, or 10 mg/kg/day sc from embryonic days (E)8 to E17 (COC 40, COC20, and COC10, respectively), vehicle-injected dams allowed access to food ad libitum (SAL) or pair-fed with the COC 40 dams (SPF 40), animals pretreated with the short-acting alpha-adrenergic antagonist phentolamine prior to each cocaine injection (P COC 40), and animals administered phentolamine prior to saline (PHENT). COC 40, P COC 40, and SPF 40 dams demonstrated the lowest percentage weight gain during gestation. The surrogate-fostered offspring of COC 40, P COC 40, and SPF 40 dams demonstrated transient brain and body growth retardation on postnatal days (P)1 and P9 when compared to pups born to SAL dams. We conducted behavioral tests which allowed us to dissociate the indirect effect of cocaine-induced malnutrition from a direct effect of prenatal cocaine administration in altering postnatal behavior. Pups from all groups were tested for first-order Pavlovian conditioning on P9 or P12 or for the ability to ignore redundant information in a blocking paradigm on P50. Unlike the SPF 40, PHENT, and SAL controls, COC 40 and P COC 40 mice were unable to acquire an aversion to an odor previously paired with shock on P9, a learning deficit that resolved by P12. However, on P50, COC 40 mice and, to a lesser extent, P COC 40 and SPF 40 mice demonstrated a persistent behavioral deficit in our blocking paradigm, which may reflect alterations in selective attention. We discuss how these findings in our rodent model have developmental implications for human infants exposed to cocaine in utero.
Asunto(s)
Aprendizaje por Asociación/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cocaína/toxicidad , Crecimiento/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Trastornos Relacionados con Sustancias , Animales , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Niño , Condicionamiento Clásico/efectos de los fármacos , Modelos Animales de Enfermedad , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Edad Gestacional , Humanos , Lactante , Ratones , Trastornos Nutricionales/etiología , Fentolamina/farmacología , Embarazo , Complicaciones del EmbarazoRESUMEN
We have utilized a mouse model of transplacental cocaine exposure to investigate the effects of cocaine dose and gestational timing in altering brain and body growth and postnatal behavior in exposed offspring. Pregnant dams were injected with cocaine HCl at 40 mg/kg/day (COC 40) or 20 mg/kg/day (COC 20), or 10 mg/kg/day (COC 10) SC from embryonic day (E) 8 to E17, or cocaine HCl at 40 mg/kg/day SC from E8 to E13 (COC Early) or from E13 to E17 (COC Late) divided in two daily doses. COC 40 and COC Late dams, as well as dams in nutritionally paired control groups (injected with saline vehicle and pair-fed with the COC dams: SPF 40, SPF 20, SPF 10), demonstrated less weight gain than SAL controls (injected with saline vehicle and allowed access to food ad lib). The surrogate fostered offspring of COC 40 and SPF 40 dams demonstrated brain and body growth retardation [on postnatal day (P) 1 and P9] when compared to pups born to SAL dams. Offspring of COC Late, SPF 20, and SPF 10 dams demonstrated brain and body growth retardation on P1 when compared to pups born to SAL dams. Pups from all groups were tested for first-order Pavlovian conditioning on P9, or for the ability to ignore redundant information in a blocking paradigm on P50. Only COC 40 mice (i.e., offspring born to COC 40 dams) were unable to acquire an aversion to an odor previously paired with shock on P9. When compared with SAL controls, COC 40 mice (and to a less significant extent SPF 40 mice) demonstrated a persistent behavioral deficit in the blocking paradigm on P50, which may reflect alterations in selective attention. Correlation analyses indicated that the dose and gestational timing of transplacental cocaine exposure, and varying degrees of malnutrition, had effects on blocking performance, with greater prenatal cocaine exposure and increased prenatal malnutrition resulting in more significant behavioral impairments. A path regression analysis demonstrated independent and significant effects of prenatal cocaine as well as prenatal malnutrition in contributing to impaired performance in the blocking paradigm. As suggested by the clinical literature, our preclinical data support a model whereby the dose and duration of prenatal cocaine exposure have direct effects on offspring brain and body growth and on behavioral performance.
Asunto(s)
Cocaína/toxicidad , Condicionamiento Psicológico/efectos de los fármacos , Intercambio Materno-Fetal , Placenta/metabolismo , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cocaína/farmacocinética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Edad Gestacional , Masculino , Ratones , Modelos Biológicos , Trastornos Nutricionales/psicología , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Desempeño Psicomotor/efectos de los fármacosRESUMEN
To characterize the transplacental effects of cocaine on the developing brain, we have developed a mouse model of gestational cocaine exposure. Pharmacokinetic analysis revealed that cocaine and its metabolites (BE, BNE, and NC) were found in fetal brain and plasma at 30 and 120 min following SC administration to embryonic day (E) 17 pregnant Swiss Webster mice. Pregnant dams injected twice daily with cocaine HCl at 20 mg/kg SC from gestational day E8 to E17 (COC) demonstrated less food intake and lower percentage weight gain than vehicle-injected dams allowed access to food ad lib (SAL). A nutritionally paired control group of dams injected with saline vehicle and pair-fed with the COC dams (SPF) demonstrated the lowest percentage weight gain of all three groups. The surrogate fostered offspring of COC and SPF dams demonstrated persistent growth retardation [on postnatal days (P) 1, P9, and P50] and transient brain growth retardation (on P1 and P9) when compared to pups born to SAL dams. We conducted behavioral tests that allowed us to dissociate the indirect effect of cocaine-induced malnutrition from a direct effect of prenatal cocaine administration in altering postnatal behavior. Pups from all three groups were tested for first-order Pavlovian conditioning on P9 or P12, or for the ability to ignore redundant information in a blocking paradigm on P50 or P100. Unlike the SPF and SAL controls, COC mice (i.e., mice born to COC dams) were unable to acquire an aversion to an odor previously paired with shock on P9. This learning deficit was transient because on P12, COC mice trained on the same conditioning task displayed an aversion to the odor that was indistinguishable from the SPF and SAL controls. P50 and P100 COC mice (and to a lesser extent, SPF mice) demonstrated a persistent behavioral deficit in the blocking paradigm, which may reflect alterations in selective attention. We discuss how these findings in our rodent model have developmental implications for human infants exposed to cocaine in utero.
Asunto(s)
Encéfalo/efectos de los fármacos , Cocaína/toxicidad , Intercambio Materno-Fetal , Placenta/metabolismo , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/embriología , Encéfalo/metabolismo , Cocaína/análogos & derivados , Cocaína/sangre , Cocaína/metabolismo , Cocaína/farmacocinética , Condicionamiento Psicológico/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , EmbarazoRESUMEN
In a mouse model of transplacental cocaine exposure we have demonstrated alterations in brain structure and function of offspring including disturbances of brain growth, disruption of neocortical cytoarchitecture, and transient as well as persistent behavioral deficits. One mechanism by which cocaine may alter fetal brain development is through cocaine-induced alpha-adrenergic-mediated (uterine) arterial vasoconstriction. In this study pregnant Swiss Webster (SW) mice were injected with cocaine HCl (20 or 40 mg/kg, SC) without any changes evident in mean arterial blood pressure (MAP) measurements. These physiology results suggest that in our mouse model, cocaine's transplacental effects on the fetus are not due to cocaine-induced maternal vasoconstriction, nor concomitant hypoperfusion of the fetus. In a separate series of experiments, pregnant SW dams were administered cocaine HCl at 40 mg/kg/day (COC 40), 20 mg/kg/day (COC 20), or 10 mg/kg/day (COC 10) [SC, divided in two daily doses, from embryonic day (E) 8 to E17 inclusive]. Additional groups of cocaine-treated dams were administered phentolamine (5 mg/kg, SC), a short-acting alpha-adrenergic antagonist, 15 min prior to each cocaine dose (Phent COC 40, Phent COC 20, Phent COC 10). Animals born to Phent COC 40 dams demonstrated transient postnatal brain growth retardation and behavioral deficits in first-order conditioning of P9 mice comparable to mice born to COC 40 dams, which received the same regimen of cocaine injections without phentolamine pretreatment. Like COC 40 offspring, Phent COC 40 offspring also demonstrated a persistent deficit in the blocking paradigm. The behavioral and growth findings confirm and extend the physiology data, and imply that in our rodent model, alpha-adrenergic mechanisms (including maternal vasoconstriction) are unlikely to mediate these toxic effects of transplacental cocaine exposure on developing brain.