RESUMEN
RATIONALE: The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. OBJECTIVES: The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. METHODS: Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding. RESULTS: Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24-25 %, and the binding potential of [11C]raclopride was reduced by 2.8-4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum. CONCLUSIONS: A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. TRIAL REGISTRATION HTTPS://UPLOAD.UMIN.AC.JP/CGI-OPEN-BIN/CTR_E/CTR_VIEW.CGI?RECPTNO=R000009703 : UMIN000008232.
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Encéfalo/metabolismo , Estado de Conciencia/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Mazindol/farmacología , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Cuerpo Estriado/metabolismo , Despersonalización/inducido químicamente , Dopamina/metabolismo , Antagonistas de Dopamina , Humanos , Masculino , Tomografía de Emisión de Positrones , Racloprida , Adulto JovenRESUMEN
OBJECTIVE: To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[(11) C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed. RESULTS: Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p < 0.05, p < 0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p < 0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC = 0.989, 95% CI: 0.965-1.000). CONCLUSIONS: Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD.
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Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Análisis de Varianza , Estudios de Casos y Controles , Corteza Cerebral/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , Persona de Mediana Edad , Piperidinas , Curva ROCRESUMEN
We present a new picture that the α-linear-chain structure for 12C and 16O has one-dimensional α condensate character. The wave functions of linear-chain states that are described by superposing a large number of Brink wave functions have extremely large overlaps of nearly 100% with single Tohsaki-Horiuchi-Schuck-Röpke wave functions, which were proposed to describe the α condensed "gaslike" states. Although this new picture is different from the conventional idea of the spatial localization of α clusters, the density distributions are shown to have localized α clusters due to the inter-α Pauli repulsion.
RESUMEN
Weight gain has been identified as being responsible for increased morbidity and mortality rates of schizophrenia patients. For the management of weight gain, exercise is one of the most acknowledged interventions. At the same time, exercise and sports have been recognized for their positive impact on psychiatric symptoms of schizophrenia. However, the neurobiological basis for this remains poorly understood. We aimed to examine the effect of sports participation on weight gain, psychiatric symptoms and brain activation during sports observation in schizophrenia patients. Thirteen schizophrenia patients who participated in a 3-month program, including sports participation and 10 control schizophrenia patients were studied. In both groups, body mass index (BMI), Positive and Negative Syndrome Scale (PANSS), and brain activation during observation of sports-related actions measured by functional magnetic resonance imaging were accessed before and after a 3-month interval. BMI and general psychopathology scale of PANSS were significantly reduced in the program group but not in the control group after a 3-month interval. Compared with baseline, activation of the body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex during observation of sports-related actions was increased in the program group. In this group, increase in EBA activation was associated with improvement in the general psychopathology scale of PANSS. Sports participation had a positive effect not only on weight gain but also on psychiatric symptoms in schizophrenia. EBA might mediate these beneficial effects of sports participation. Our findings merit further investigation of neurobiological mechanisms underlying the therapeutic effect of sports for schizophrenia.
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Nivel de Alerta/fisiología , Baloncesto/fisiología , Ejercicio Físico/fisiología , Lóbulo Occipital/fisiopatología , Esquizofrenia/fisiopatología , Esquizofrenia/terapia , Psicología del Esquizofrénico , Lóbulo Temporal/fisiopatología , Percepción Visual/fisiología , Adulto , Índice de Masa Corporal , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Esquizofrenia/diagnóstico , Grabación en Video , Aumento de Peso/fisiologíaRESUMEN
OBJECTIVE: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). METHODS: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. RESULTS: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. CONCLUSIONS: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.
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Acetilcolina/deficiencia , Acetilcolinesterasa/metabolismo , Núcleo Basal de Meynert/enzimología , Fibras Colinérgicas/enzimología , Enfermedad por Cuerpos de Lewy/enzimología , Enfermedad de Parkinson/enzimología , Acetilcolinesterasa/análisis , Anciano , Núcleo Basal de Meynert/diagnóstico por imagen , Núcleo Basal de Meynert/patología , Biomarcadores/análisis , Biomarcadores/metabolismo , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Fibras Colinérgicas/patología , Estudios de Cohortes , Diagnóstico Diferencial , Progresión de la Enfermedad , Regulación hacia Abajo/fisiología , Humanos , Inmunohistoquímica , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/patología , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/metabolismo , Lóbulo Occipital/patología , Lóbulo Occipital/fisiopatología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , CintigrafíaRESUMEN
AIM: Inter-individual variations in normal human cerebral blood flow (CBF) at rest condition have been reported. Inter-individual variation of cerebral vascular tone is considered to contribute to this, and several determinants of cerebral vascular tone have been proposed. In the present study, the relationship between CBF and cerebral vascular tone to inter-individual variation at rest condition was investigated using positron emission tomography (PET). METHODS: CBF was measured using PET with H(2) (15)O in each of 20 healthy subjects (20-28 years) under three conditions: at rest (baseline), during hypercapnia and during hypocapnia. The vascular response to change in P(a)CO(2) was calculated as the percentage changes in CBF per absolute change in P(a)CO(2) in response to hypercapnia and hypocapnia. RESULTS: A significant negative correlation between baseline CBF and the vascular response to hypocapnia was observed in the thalamus, temporal cortex, parietal cortex, occipital cortex and cerebral cortex (P < 0.05). A trend towards negative correlation between baseline CBF and the vascular response to hypocapnia was observed in the cerebellum and putamen (P < 0.1). A significant negative correlation between baseline CBF and the vascular response to hypercapnia was observed in the occipital cortex (P < 0.05). No significant correlation was observed between baseline CBF and haemoglobin concentration, and P(a)CO(2). CONCLUSION: These findings support the assumption that cerebral vascular tone might incline towards vasoconstriction and vasodilatation when baseline CBF is low and high between individuals respectively. Although several determinants of cerebral vascular tone have been proposed, the mechanism of such inter-individual differences in cerebral vascular tone is unknown.
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Dióxido de Carbono/sangre , Circulación Cerebrovascular/fisiología , Adulto , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Humanos , Concentración de Iones de Hidrógeno , Hipercapnia/diagnóstico por imagen , Hipercapnia/fisiopatología , Hipocapnia/diagnóstico por imagen , Hipocapnia/fisiopatología , Masculino , Oxígeno/sangre , Presión Parcial , Tomografía de Emisión de Positrones , Vasoconstricción/fisiología , Vasodilatación/fisiología , Sistema Vasomotor/fisiologíaRESUMEN
A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields affect malignant transformation or other cellular stress responses. Our group previously reported that DNA strand breaks were not induced in human cells exposed to 2.1425 GHz Wideband Code Division Multiple Access (W-CDMA) radiation up to 800 mW/kg from mobile radio base stations employing the IMT-2000 cellular system. In the current study, BALB/3T3 cells were continuously exposed to 2.1425 GHz W-CDMA RF fields at specific absorption rates (SARs) of 80 and 800 mW/kg for 6 weeks and malignant cell transformation was assessed. In addition, 3-methylcholanthrene (MCA)-treated cells were exposed to RF fields in a similar fashion, to assess for effects on tumor promotion. Finally, the effect of RF fields on tumor co-promotion was assessed in BALB/3T3 cells initiated with MCA and co-exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). At the end of the incubation period, transformation dishes were fixed, stained with Giemsa, and scored for morphologically transformed foci. No significant differences in transformation frequency were observed between the test groups exposed to RF signals and the sham-exposed negative controls in the non-, MCA-, or MCA plus TPA-treated cells. Our studies found no evidence to support the hypothesis that RF fields may affect malignant transformation. Our results suggest that exposure to low-level RF radiation of up to 800 mW/kg does not induce cell transformation, which causes tumor formation.
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Teléfono Celular , Transformación Celular Neoplásica/efectos de la radiación , Ondas de Radio , Células 3T3 , Animales , Carcinógenos/toxicidad , Metilcolantreno/toxicidad , Ratones , Ratones Endogámicos BALB CRESUMEN
A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields induce apoptosis or other cellular stress response that activate p53 or the p53-signaling pathway. First, we evaluated the response of human cells to microwave exposure at a specific absorption rate (SAR) of 80 mW/kg, which corresponds to the limit of the average whole-body SAR for general public exposure defined as a basic restriction by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. Second, we investigated whether continuous wave (CW) and wideband code division multiple access (W-CDMA) modulated signal RF fields at 2.1425 GHz induced apoptosis or any signs of stress. Human glioblastoma A172 cells were exposed to W-CDMA radiation at SARs of 80, 250, and 800 mW/kg, and CW radiation at 80 mW/kg for 24 or 48 h. Human IMR-90 fibroblasts from fetal lungs were exposed to both W-CDMA and CW radiation at a SAR of 80 mW/kg for 28 h. Under the RF field exposure conditions described above, no significant differences in the percentage of apoptotic cells were observed between the test groups exposed to RF signals and the sham-exposed negative controls, as evaluated by the Annexin V affinity assay. No significant differences in expression levels of phosphorylated p53 at serine 15 or total p53 were observed between the test groups and the negative controls by the bead-based multiplex assay. Moreover, microarray hybridization and real-time RT-PCR analysis showed no noticeable differences in gene expression of the subsequent downstream targets of p53 signaling involved in apoptosis between the test groups and the negative controls. Our results confirm that exposure to low-level RF signals up to 800 mW/kg does not induce p53-dependent apoptosis, DNA damage, or other stress response in human cells.
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Expresión Génica/efectos de la radiación , Ondas de Radio , Proteína p53 Supresora de Tumor/biosíntesis , Secuencia de Aminoácidos , Apoptosis/efectos de la radiación , Línea Celular , Línea Celular Tumoral , Fibroblastos/efectos de la radiación , Glioblastoma , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación/efectos de la radiación , Serina/metabolismo , Proteína p53 Supresora de Tumor/efectos de la radiaciónRESUMEN
Epidemiologic studies show that smokers with a past history of depression are more likely to relapse into depression after smoking cessation than those without a history of depression. These studies suggest the existence of a direct biological link between nicotine withdrawal and depression. To investigate the neuronal and hormonal mechanisms of the precipitation of depression during smoking cessation, we used an animal model of nicotine withdrawal and studied the function of the hypothalamic-pituitary-adrenal (HPA) axis, the abnormality of which is implicated in the pathogenesis of depression. Rats were implanted with a minipump delivering nicotine at 6.0 mg/kg/day for 12 days. The minipumps were removed in order to abruptly terminate nicotine infusion. The activity of the HPA axis was determined on day 2 of withdrawal using the stress-induced corticosterone response and the dexamethasone suppression test (DST). At the same time the expressions of glucocorticoid receptor (GR) mRNA in the hippocampus and paraventricular nucleus of hypothalamus (PVN) and corticotropin-releasing hormone (CRH) mRNA in PVN were determined by non-radioactive in situ hybridization. Nicotine withdrawal resulted in lower corticosterone levels during restraint stress, suggesting subsensitivity of the HPA axis to stress. The result of DST, however, did not show a significant difference between nicotine-withdrawal and control rats. These effects of nicotine withdrawal were not accompanied by any changes in the expressions of GR and CRH mRNA in either hippocampus or PVN. These results suggest that subsensitivity of the HPA axis to stress during nicotine withdrawal may be implicated in the precipitation of depression during smoking cessation, although GR and CRH in the HPA axis do not appear to play a significant role.
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Depresión/fisiopatología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Nicotina/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Estrés Psicológico/sangre , Síndrome de Abstinencia a Sustancias/fisiopatología , Adaptación Fisiológica , Pruebas de Función de la Corteza Suprarrenal , Animales , Corticosterona/sangre , Depresión/sangre , Depresión/complicaciones , Dexametasona/farmacología , Modelos Animales de Enfermedad , Glucocorticoides/farmacología , Hipocampo/metabolismo , Masculino , Agonistas Nicotínicos/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Wistar , Receptores de Glucocorticoides/metabolismo , Cese del Hábito de Fumar/psicología , Estrés Psicológico/complicaciones , Síndrome de Abstinencia a Sustancias/complicaciones , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
We performed in vitro and in vivo assays of the metabolism of [(11)C]Ro15-4513 over time in the plasma of mice, rats, monkeys and humans, using a radio-HPLC equipped with a sensitive positron detector, in order to compare the metabolic rates of the radiopharmaceutical agent among the different animal species and to establish a highly sensitive analytical method for the radiotracer agent. We also examined the metabolism of [(11)C]Ro15-4513 in the brain tissue of mice and rats. The analytical method used in this study permitted detection of even extremely low levels of radioactivity (approximately 5,000 dpm). In vitro experiments revealed that [(11)C]Ro15-4513 in the blood was metabolized to hydrolysate [(11)C]A. The species were classified in descending order of the metabolic rate of the radiotracer in vitro as follows; mice, rats, and monkeys/humans. In the in vitro experiment, the percentage of the unchanged drug in the plasma at 60 minutes postdose was 9% in mice, 70% in rats, 97% in monkeys, and 98% in humans. In vivo metabolite analysis in the blood showed the presence of two radioactive metabolites, consisting of one hydrolysate [(11)C]A and another unidentified substance. The species were classified in descending order of the metabolic rate of the radiotracer in vivo as follows; mice, rats/humans, and monkeys. The percentage of the unchanged drug in the plasma was 6% in mice, 21% in rats, 26% in humans, and 40% in monkeys. Furthermore, the in vitro and in vivo experiments conducted to analyze the metabolism of [(11)C]Ro15-4513 in the brain tissue of mice and rats revealed that the radiotracer was metabolized to some extent in the brain tissue of these animals. In the in vivo experiment, the percentage of the unchanged drug at 60 min postdose was 86% in the brain tissue of mice and 88% in the brain tissue of rats, while in the in vitro experiment, the corresponding percentage was 93% in mice, and 91% in rats.
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Azidas/farmacocinética , Benzodiazepinas/farmacocinética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Técnica de Dilución de Radioisótopos , Tomografía Computarizada de Emisión/métodos , Animales , Azidas/sangre , Benzodiazepinas/sangre , Radioisótopos de Carbono/farmacocinética , Haplorrinos , Humanos , Tasa de Depuración Metabólica , Ratones , Especificidad de Órganos , Radiofármacos/sangre , Radiofármacos/farmacocinética , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiology and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concentrations of D2 receptors in extrastriatal regions using positron emission tomography (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a reference tissue model. Eight healthy male subjects (aged 20-33 years) underwent two [11C]FLB 457 PET examinations. Radioactivity in the cerebellum was used as the reference. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calculated using the reference tissue model. The BP was also calculated for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quantitative evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual.
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Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Dopamina D2/análisis , Salicilamidas/farmacocinética , Adulto , Encéfalo/metabolismo , Radioisótopos de Carbono/uso terapéutico , Antagonistas de Dopamina/farmacocinética , Humanos , Masculino , Ensayo de Unión Radioligante , Reproducibilidad de los Resultados , Tomografía Computarizada de EmisiónRESUMEN
When using a tool, we can perceive a psychological association between the tool and the body parts-the tool is incorporated into our "body-image." During tool use, visual response properties of bimodal (tactile and visual) neurons in the intraparietal area of the monkey's cerebral cortex were modified to include the hand-held tool. Visual properties of the monkey intraparietal neurons may represent the body-image in the brain. We explored tool use-induced activation within the intraparietal area and elsewhere in alert monkey brain using positron emission tomography (PET). Tool use-related activities compared with the control condition (simple-stick manipulation) revealed a significant increase in cerebral blood flow in the corresponding intraparietal region, basal ganglia, presupplementary motor area, premotor cortex, and cerebellum. These tool use-specific areas may participate in maintaining and updating the body-image for the precise guidance of a hand-held rake onto a distant reward.
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Mapeo Encefálico , Encéfalo/fisiología , Lóbulo Parietal/fisiología , Desempeño Psicomotor/fisiología , Tomografía Computarizada de Emisión , Animales , Encéfalo/irrigación sanguínea , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Macaca , Masculino , Lóbulo Parietal/irrigación sanguínea , Solución de Problemas/fisiología , Flujo Sanguíneo Regional/fisiologíaRESUMEN
Although the aging effect of dopamine D2 receptor in the striatum is well-documented, the effect of age on the extrastriatal dopamine D2 receptor has not been fully examined. Since the density of extrastriatal dopamine D2 receptor is very low, suitable ligands are limited. In this study, we used [11C]FLB 457 to quantify the extrastriatal dopamine D2 receptor in the living human brain. Twenty-seven healthy male subjects aged from 21 to 82 years participated in the positron emission tomography study. Extrastriatal [11C]FLB 457 binding was quantified with a reference tissue model using cerebellum as a reference region. Binding potentials corresponding to Bmax/Kd were used to evaluate age-related change. We found age-related decreases of D2 receptor binding in all measured extrastriatal regions. The decrease of D2 receptor binding was 13.8% per decade in frontal cortex, 12.0% in temporal cortex, 13.4% in parietal cortex, 12.4% in occipital cortex, 12.2% in hippocampus, and 4.8% in thalamus. These findings suggest that the amounts of D2 receptor declines in all brain regions as part of the normal aging process.
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Envejecimiento/metabolismo , Cuerpo Estriado/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Radioisótopos de Carbono , Cuerpo Estriado/diagnóstico por imagen , Antagonistas de Dopamina , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas , Receptores de Dopamina D2/análisis , Salicilamidas , Tomografía Computarizada de EmisiónRESUMEN
Fas is constitutively expressed on endothelial cells, but in contrast to smooth muscle and other cell types, endothelial cells are highly resistant to Fas-mediated apoptosis. In this study, we examined the role of the serine/threonine kinase Akt/PKB in controlling the sensitivity of endothelial cells to Fas-mediated apoptosis. Serum deprivation inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP), which functions downstream from Fas. FLIP expression levels were restored when serum-depleted cells were treated with vascular endothelial growth factor. Treatment with the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors wortmannin or LY294002 or infection of the adenoviral construct expressing dominant-negative Akt (Adeno-dnAkt) also inhibited the expression of FLIP in endothelial cells, whereas the MEK inhibitor PD98059 had no effect. Conversely, adenovirus-mediated transfection of a constitutively-active Akt gene abolished the wortmannin- and LY294002-mediated downregulation of FLIP. Suppression of PI 3-kinase signaling sensitized endothelial cells to Fas-mediated apoptosis. Under conditions of suppressed PI 3-kinase signaling, restoration of FLIP expression reversed the induced sensitivity of endothelial cells to Fas-mediated apoptosis. These data suggest that inhibition of Fas-mediated apoptosis, via promotion of FLIP expression, is a mechanism through which Akt signaling can promote endothelial cell survival.
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Apoptosis , Proteínas Portadoras/metabolismo , Endotelio Vascular/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/fisiología , Receptor fas/fisiología , Androstadienos/farmacología , Anticuerpos/inmunología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Caspasa 8 , Caspasa 9 , Caspasas/metabolismo , Células Cultivadas , Regulación hacia Abajo , Factores de Crecimiento Endotelial/farmacología , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Precursores Enzimáticos/metabolismo , Humanos , Células Jurkat , Linfocinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Tetraciclina/farmacología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Wortmanina , Receptor fas/inmunologíaRESUMEN
Central dopaminergic systems are known to be implicated in the pathophysiology of schizophrenia and recent in vivo dopamine receptor imaging studies have focused on the measurement of extrastriatal dopamine receptor. However, there are only a limited number of ligands that can measure the low-density D2 receptor in extrastriatal regions and their sensitivity to endogenous dopamine in extrastriatal regions has not yet been fully examined. In this study, the effect of endogenous dopamine on the extrastriatal binding of [11C]FLB 457 was examined in the rhesus monkey after facilitation with 1 mg/kg of methamphetamine (MAP) and was compared with the effect on the striatal binding of [11C]raclopride. The indices of receptor binding were obtained by four methods using cerebellum as a reference region. The bindings of [11C]FLB 457 in the frontal cortex, temporal cortex, and thalamus were not significantly changed after MAP treatment, while the striatal binding of [11C]raclopride was decreased by more than 20%. These results suggest that [11C]FLB 457 is not sensitive to endogenous dopamine in the extrastriatal regions of rhesus monkeys, despite a sufficient dose of MAP to decrease the binding of [11C]raclopride in the striatum.
Asunto(s)
Encéfalo/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Dopamina/metabolismo , Interacciones Farmacológicas/fisiología , Neuronas/efectos de los fármacos , Pirrolidinas/metabolismo , Salicilamidas/metabolismo , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Encéfalo/metabolismo , Mapeo Encefálico , Radioisótopos de Carbono/farmacología , Dopaminérgicos/farmacología , Macaca mulatta , Masculino , Metanfetamina/farmacología , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neuronas/metabolismo , Racloprida/farmacología , Ensayo de Unión Radioligante , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Reproducibilidad de los Resultados , Tomografía Computarizada de EmisiónRESUMEN
Positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies have demonstrated consistent findings of high dopamine D2 receptor occupancy (> 65-70%) in patients treated with antipsychotic drugs. Further, the risk of extrapyramidal side effects has been shown high in patients with occupancy above 80%. On the basis of these findings, an optimal interval for D2 receptor occupancy between 70% and 80% has been suggested. It has also been shown that several atypical antipsychotics induce marked occupancy of central 5-HT2 and D2 receptors in vivo. However, a low D2 occupancy has been observed in patients with clinical dose of clozapine or quetiapine. The antipsychotic effect of these atypical drugs with a low D2 receptor occupancy has been widely discussed with respect to actions on other receptor systems, limbic selectivity of antipsychotic action and episodic transient occupancy. The recent advances in PET/SPECT and developments of new radioligands have made it possible to evaluate antipsychotic drug actions directly in humans. The empirical data from occupancy measurements will enable us to open future directions of investigation of antipsychotic action and improvement of antipsychotic treatment.
Asunto(s)
Antipsicóticos/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada de Emisión , Animales , HumanosRESUMEN
Lithium salts have been widely used in the treatment of mood disorders, but the mechanism of action is still not clear. In this work, a methodology for two-dimensional Lithium-7 imaging on clinical systems is presented. The data were acquired using a phosphorus volume head coil that was re-tuned for the Lithium-7 frequency. A spectroscopic sequence was used to acquire the free induction decay (FID) after volume excitation using a hard pulse. The results obtained on the head of patients undergoing lithium treatment (n = 7, 0.6 mEq/l average serum level) demonstrate that images of adequate signal to noise ratio (100:1) can be obtained in acceptable imaging times (55 min) using the proposed methodology. The distribution of 7Li appears uniform in the brains of the patients studied.
Asunto(s)
Encéfalo/patología , Isótopos , Litio , Imagen por Resonancia Magnética/métodos , Humanos , Fantasmas de Imagen , Espectrofotometría/métodos , Factores de TiempoRESUMEN
Inclusion body myositis (sIBM) is the most common disorder of skeletal muscle in aged humans. It shares biochemical features with Alzheimer's disease, including congophilic deposits, which are immunoreactive for beta-amyloid peptide (Abeta) and C'-terminal betaAPP epitopes. However, the etiology of myofiber loss and the role of intracellular Abeta in IBM is unknown. Here we report correlative evidence for apoptotic cell death in myofibers of IBM patients that exhibit pronounced Abeta deposition. HSV-1-mediated gene transfer of Abeta(42) into cultured C2C12 myotubes resulted in a 12.6-fold increase in dUTP-labeled and condensed nuclei over nonexpressing myotubes (P < 0.05). The C'-terminal betaAPP domain C99 also induced myotube apoptosis, but to a significantly lesser extent than Abeta. Apoptosis specific to Abeta-expressing myotubes was also demonstrated through DNA fragmentation, decreased mitochondrial function and the loss of membrane phospholipid polarity. Myotubes laden with Abeta(42), but not other transgene products, developed cytoplasmic inclusions consisting of fibrillar material. Furthermore, injection of normal mouse gastrocnemius muscle with HSV-encoding Abeta cDNA resulted in TUNEL-positive myofibers with pyknotic nuclei. We conclude that Abeta is sufficient to induce apoptosis in myofibers both in vivo and in vitro and suggest it may contribute to myofiber loss and muscle dysfunction in patients with IBM.
Asunto(s)
Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Apoptosis/genética , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Miositis por Cuerpos de Inclusión/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/patología , Células Cultivadas/metabolismo , Células Cultivadas/patología , Células Cultivadas/ultraestructura , Fragmentación del ADN/genética , ADN Complementario/farmacología , Técnicas de Transferencia de Gen , Vectores Genéticos , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Microscopía Electrónica , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/ultraestructura , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/fisiopatología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Estructura Terciaria de Proteína/genética , Simplexvirus/genéticaRESUMEN
Human personality has been considered to have a neurochemical background. We examined the relation between extrastriatal dopamine D2 receptor binding in living human brain and the personality trait of novelty seeking that has been proposed to be related to dopaminergic function in the brain. We measured extrastriatal dopamine D2 receptors of 24 healthy young male subjects using [(11)C]FLB 457 positron emission tomography. The personality trait of each subject was assessed by the Temperament and Character Inventory (TCI). Correlation of dopamine D2 receptor binding with novelty seeking was calculated using region-of-interest analysis and statistical parametric mapping based on the binding potential images generated using a reference tissue model. A significant negative correlation was observed between binding potential values and the novelty seeking scores on TCI in the right insular cortex. No significant correlation was observed in any other region. Our result indicates that there is a significant association between dopamine D2 receptor binding and the human novelty seeking trait in the right insular cortex.