RESUMEN
BACKGROUND: Despite massive research on weight gain and metabolic complications in schizophrenia there are few studies on energy expenditure and no current data on physical capacity. AIM: To determine oxygen uptake capacity, respiratory quotient (RQ) and energy expenditure during a submaximal exercise test in patients with schizophrenia and healthy controls. METHOD: Ten male patients and 10 controls were included. RQ and energy expenditure were investigated with indirect calorimetry during a cycle ergometer test. The submaximal work level was defined by heart rate and perceived exhaustion. Physical capacity was determined from predicted maximal oxygen uptake capacity (VO(2-max)). RESULTS: The patients exhibited significantly higher RQ on submaximal workloads and lower physical capacity. A significant lower calculated VO(2-max) remained after correction for body weight and fat free mass (FFM). Energy expenditure did not differ on fixed workloads. CONCLUSION: RQ was rapidly increasing in the patients during exercise indicating a faster transition to carbohydrate oxidation and anaerobic metabolism that also implies a performance closer to maximal oxygen uptake even at submaximal loads. This may restrict the capacity for everyday activity and exercise and thus contribute to the risk for weight gain. Physical capacity was consequently significantly lower in the patients.
Asunto(s)
Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Consumo de Oxígeno/fisiología , Esquizofrenia/fisiopatología , Adulto , Prueba de Esfuerzo , Humanos , Masculino , Persona de Mediana Edad , Aptitud Física/fisiologíaRESUMEN
Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n=10) and healthy controls (n=10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (V(max)) and affinity constant (K(m)) were determined. A significantly lower V(max) for tyrosine (p=0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K(m) for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V(max)) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.
Asunto(s)
Trastorno Bipolar/metabolismo , Trastorno Bipolar/patología , Fibroblastos/metabolismo , Piel/metabolismo , Triptófano/metabolismo , Tirosina/metabolismo , Adulto , Transporte Biológico Activo/fisiología , Células Cultivadas , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: A lowered energy metabolism in schizophrenia was reported already in the 1920s. However, these early investigations were case studies without control groups or statistical analysis. In this study the resting energy expenditure (REE) and relevant body composition variables were measured in patients with schizophrenia and healthy controls. METHOD: REE was determined in 30 patients and 17 controls. The difference between the measured and the expected level for each individual was calculated as DeltaREE. Body composition was assessed with bioelectrical impedance and calliper measurements. RESULTS: DeltaREE was significantly lower in the patients than in the controls. A decrease was also seen in the non-medicated patients. The patients showed significantly lower percentages of water in fat free-mass and intracellular water. CONCLUSION: The lowering of REE and body water fractions may suggest a homeostatic aberration in schizophrenia that may be of importance for the understanding of metabolic disturbances observed in the disease.
Asunto(s)
Composición Corporal/fisiología , Metabolismo Energético/fisiología , Esquizofrenia/fisiopatología , Adulto , Agua Corporal/metabolismo , Calorimetría Indirecta , Impedancia Eléctrica , Femenino , Humanos , Masculino , Valores de Referencia , Descanso/fisiología , Esquizofrenia/diagnóstico , Grosor de los Pliegues CutáneosRESUMEN
Patients with schizophrenia have in different studies shown reduced niacin sensitivity and lower electrodermal activity (EDA) after auditory stimulation. Peripheral mediation of prostaglandins may have a physiological role in both responses. This motivates study of both niacin response and electrodermal responding in the same patients with schizophrenia. Thirty patients with schizophrenia and 17 controls were investigated with EDA and thereafter given 200mg niacin orally with continuous assessment of skin temperature. The patients showed a delayed temperature increase after niacin ingestion (P=0.002) and a higher frequency of electrodermal non-responding (P<0.05). Response/non-response for niacin correlated with EDA response/non-response in the patient group (P=0.009). The niacin test revealed a slower vasodilation reaction in the patients. The association between response patterns for the niacin test and EDA suggests that a common aberration in skin physiology may be of importance for both reactions in schizophrenia.
Asunto(s)
Rubor/inducido químicamente , Respuesta Galvánica de la Piel/efectos de los fármacos , Niacina/farmacología , Esquizofrenia/fisiopatología , Administración Oral , Adulto , Femenino , Respuesta Galvánica de la Piel/fisiología , Humanos , Masculino , Niacina/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Piel/efectos de los fármacos , Piel/fisiopatología , Temperatura Cutánea/efectos de los fármacos , Complejo Vitamínico B/administración & dosificación , Complejo Vitamínico B/farmacologíaRESUMEN
BACKGROUND: There is evidence that patients with schizophrenia exhibit abnormalities, not only in the brain but also in peripheral organs. An abnormal cell membrane composition has been suggested to be a common denominator, supported by findings of alterations in membrane phospholipid levels. In a previous study, the transport of amino acids across the plasma membrane was investigated with fibroblasts from patients with schizophrenia and controls. An isolated decrease in the maximal transport capacity (V(max)) of tyrosine was observed in the cells from patients. In this context, tyrosine transport across the fibroblast membrane was investigated in patients with schizophrenia and healthy control subjects. METHODS: Skin fibroblasts were obtained from 36 patients with schizophrenia (15 first episode and 21 chronic) and 10 healthy controls. Tyrosine transport across the cell membrane was studied in cultivated fibroblasts. The V(max) and the affinity of the tyrosine binding sites (K(m)) were determined. RESULTS: Significantly lower V(max) (F(1,41) = 12.80; P =.001; effect size = 1.36) and K(m) (F(1,41) = 24.85; P<.001; effect size = 1.00) were observed in fibroblasts from the patients. The findings were present in both neuroleptic-naive patients with their first episode and patients with chronic schizophrenia. CONCLUSIONS: The lower V(max) and K(m) are compatible with a cell membrane disturbance and support the view of schizophrenia as a systemic disorder. The decreased V(max) and K(m) observed in cells from schizophrenic patients probably reflect a genetic trait, as the changes were transmitted through several cell generations of cultured fibroblast.
Asunto(s)
Membrana Celular/metabolismo , Esquizofrenia/metabolismo , Tirosina/metabolismo , Adulto , Edad de Inicio , Transporte Biológico/genética , Células Cultivadas , Familia/psicología , Femenino , Fibroblastos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Esquizofrenia/diagnóstico , Esquizofrenia/genéticaRESUMEN
In previous studies of schizophrenic patients, neuromuscular (histopathological and electrophysiological) and psychomotor (finger tapping) abnormalities were found. The present study was designed to investigate relationships between these abnormalities and a family history of psychosis in 14 schizophrenic patients and 25 unaffected first-degree relatives compared to 14 healthy controls. Muscle biopsies were performed in either m. tibialis anterior or m. lateralis. Macro EMG recordings were made from m. tibialis anterior. A finger tapping test was used to investigate psychomotor performance. Neuromuscular abnormalities (muscle biopsies and/or macro EMG) and/or aberrant psychomotor performance (finger tapping test) were found in 13 (93%) patients, 14 (56%) first-degree relatives and in three (21%) controls. A statistically significant relationship for the psychomotor, but not neuromuscular changes to a family history of psychosis was found using a logistic regression method. The percentage of patients, relatives and healthy controls exhibiting were 36/40/7% in the muscle biopsy, 50/20/0% in the macro EMG, and 71/82/14% in the finger tapping investigations. A higher frequency of neuromuscular and psychomotor abnormalities was found in patients with schizophrenia and their first-degree relatives compared to healthy controls. The relationship between psychomotor findings and a family history of psychosis indicate that central aspects of motor aberrations are associated with a hereditary disposition of psychosis. The neuromuscular as well as psychomotor changes indicate that schizophrenia may be a systemic disease involving the central nervous system as well as peripheral organs. An altered cell membrane is suggested to be an underlying factor based on the type of neuromuscular findings.
Asunto(s)
Enfermedades Neuromusculares/complicaciones , Trastornos Psicomotores/complicaciones , Esquizofrenia/complicaciones , Adulto , Anciano , Atrofia/patología , Biopsia , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/patología , Enfermedades Neuromusculares/diagnóstico , Trastornos Psicomotores/diagnósticoRESUMEN
BACKGROUND: In a previous study of motor unit properties in patients with schizophrenia, muscle fiber histologic and electrophysiologic abnormalities were observed. The present study was designed to compare patients with schizophrenia with healthy control subjects with regard to muscle fiber histology and motor unit function. A second objective was to relate these variables to clinical characteristics. METHODS: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSM-III-R) and 27 matched control subjects were included in the study. Muscle biopsies were performed either in m. tibialis anterior or m. vastus lateralis. Electromyographic recordings (macro EMG) were made from the m. tibialis anterior motor units. Psychiatric ratings included the PANSS and extrapyramidal side effects. RESULTS: Seven of the muscle biopsy specimens from the patients and one from the control subjects were classified as abnormal (p =.049). The most frequent abnormality was atrophic muscle fibers. Eight patients and no control subjects exhibited pathological macro EMG (p =.032). The findings were present in chronic as well as in first-episode patients with schizophrenia. CONCLUSIONS: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle biopsy or the macro EMG investigations. The results indicate that either a common pathologic process or different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane function.
Asunto(s)
Electromiografía , Neuronas Motoras/patología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Enfermedad Aguda , Adulto , Atrofia , Biopsia , Estudios de Casos y Controles , Membrana Celular/metabolismo , Enfermedad Crónica , Femenino , Humanos , Masculino , Esquizofrenia/metabolismoRESUMEN
Previous PET studies of tyrosine transport have suggested that the transport of tyrosine from blood to brain compartment is not dependent on its plasma concentration in patients with schizophrenia. In order to examine this relationship, the transport constant (K1) of tyrosine was determined in five patients with schizophrenia and five normals. L-[1-11C]Tyrosine was injected i.v. and arterial blood samples were taken during PET scanning. The tyrosine transport was assessed during baseline conditions and after oral administration of L-tyrosine at a dose (175 mg/kg) that significantly elevated the plasma levels. K1 was determined from tracer kinetic modelling. The transport rate dropped in the normals after tyrosine loading, which is consistent with the prevailing notion that the brain transport system for neutral amino acids works close to saturation, whereas it was virtually unchanged in the schizophrenics. The results demonstrated that tyrosine transport was not saturated in the patients with schizophrenia and thus could lead to elevated brain concentrations of tyrosine.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Esquizofrenia/metabolismo , Tirosina/metabolismo , Transporte Biológico/fisiología , Membrana Celular/metabolismo , Humanos , Modelos Biológicos , Tomografía Computarizada de EmisiónRESUMEN
The purpose of the present experiment was to test the possibility that atypical antipsychotics and classical antipsychotics differentially regulate specific neurochemical processes within the entopeduncular nucleus. For these experiments, rats were administered clozapine (25 mg/kg), haloperidol (1 mg/kg), or Tween-80 (control) daily for 21 days. Dopamine D(1)-receptor binding was assessed with in vitro receptor autoradiographic methods and the mRNAs corresponding to the two forms of glutamate decarboxylase (glutamate decarboxylase-65 and glutamate decarboxylase-67) were analyzed using in situ hybridization histochemical methods. In addition, vacuous chewing movements (VCM) were measured throughout the drug administration period as a functional indicator of drug action and changes in striatal dopamine D(2)-receptor binding were measured as a positive control for D(2)-receptor antagonist properties of haloperidol and clozapine. In agreement with previous reports, haloperidol increased D(2)-receptor binding throughout the striatum while clozapine had a more limited impact on D(2)-receptors. Behavioral analysis revealed that both haloperidol and clozapine enhanced the display of vacuous chewing movements to a similar extent but with a different postinjection latency. In the entopeduncular nucleus, clozapine increased D(1)-receptor binding compared to controls while haloperidol was without effect. With respect to the regulation of GAD mRNAs, haloperidol increased glutamate decarboxylase-65 and glutamate decarboxylase-67 mRNA levels throughout the entopeduncular nucleus. The effects of clozapine were restricted to increases in glutamate decarboxylase-65 mRNA. These studies show that clozapine and haloperidol, both of which increase the occurrence of VCM, differentially modulate the neurochemistry of the entopeduncular nucleus.
Asunto(s)
Clozapina/farmacología , Núcleo Entopeduncular/química , Núcleo Entopeduncular/efectos de los fármacos , Haloperidol/farmacología , Masticación/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Animales , Antipsicóticos/farmacología , Autorradiografía , Benzazepinas/análogos & derivados , Benzazepinas/farmacología , Sitios de Unión/fisiología , Unión Competitiva/fisiología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Núcleo Entopeduncular/fisiología , Femenino , Glutamato Descarboxilasa/genética , Hibridación in Situ , Masticación/fisiología , Neostriado/química , Neostriado/efectos de los fármacos , Neostriado/fisiología , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Salicilamidas/farmacología , Factores de TiempoRESUMEN
Schizophrenic patients (DSM-III-R) were consecutively recruited and 39 were included. Twenty-one were first-episode and 18 were chronic schizophrenic patients. Thirty of the patients were on neuroleptic medication. Thirty-three parents were included, of whom nine were classified as 'family history positive' and 22 as 'family history negative' of a disposition to psychosis. Fifty-five healthy controls volunteered. The subjects were investigated according to a protocol divided into neurological signs and psychomotor performance (finger-tapping rate, Purdue pegboard test, pronation-supination test, gait and hand-grasp strength). Seventy-eight percent of the patients and 7% of the controls were classified as globally aberrant in signs. The patients and their parents, classified as 'family history positive', exhibited a similar laterality pattern in a finger-tapping test improving performance with the preferred hand, significantly different from the performance of the 'family history negative' parents and normal subjects. Duration of illness, neuroleptic medication and negative symptoms were not related to the occurrence of neurological signs and psychomotor performance. These findings indicate that neurological aberrations are present at the onset of illness and that hereditary factors are associated with motor laterality.
Asunto(s)
Predisposición Genética a la Enfermedad/fisiopatología , Examen Neurológico , Desempeño Psicomotor/fisiología , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatología , Enfermedad Aguda , Adolescente , Adulto , Análisis de Varianza , Enfermedad Crónica , Familia , Femenino , Lateralidad Funcional , Humanos , Masculino , Anamnesis , Persona de Mediana EdadRESUMEN
The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D2 dopamine receptor was investigated using the PET tracers [11C]raclopride and N-[11C]methylspiperone in a group of five schizophrenic patients. A steady-state treatment condition was ensured by dosing the patients with 750 mg quetiapine daily during 3 weeks followed by a period of tapering off the dose. For each patient, PET examinations were performed with both tracers at two of the following doses: 750, 450, 300 and/or 150 mg. As control, a group of six healthy untreated volunteers was investigated. The D2 binding potential in the putamen and the caudate nucleus was determined by using an evaluation method based on the method proposed by Patlak and Blasberg. The receptor occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing quetiapine dose (reaching 51% +/- 10% occupancy at the 750 mg dose) was detected with [11C]raclopride (P < 0.01), no such trend was apparent for N-[11C]methylspiperone (P > 0.09, maximal occupancy values were 2% +/- 3%, measured for the group of three patients on 450 mg). The study suggests that N-[11C]methylspiperone cannot be used for the assessment of D2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants.
Asunto(s)
Antipsicóticos/metabolismo , Dibenzotiazepinas/metabolismo , Receptores de Dopamina D2/metabolismo , Salicilamidas , Espiperona/análogos & derivados , Tomografía Computarizada de Emisión , Adulto , Núcleo Caudado/metabolismo , Cerebelo/metabolismo , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Putamen/metabolismo , Fumarato de Quetiapina , Racloprida , Esquizofrenia/metabolismoRESUMEN
Dopamine D1-receptor binding in the basal ganglia is differentially regulated by subtype nonspecific dopamine antagonists such as the antipsychotic, Fluphenazine. The purpose of the present study was to determine the relative contributions of D1 and D2 receptor systems in the regulation of basal ganglia D1-receptor binding. Rats were injected twice daily for 21 days with saline, the D1-receptor antagonist, SCH-23390, the D2-receptor antagonist, Raclopride, or both SCH-23390 and Raclopride. Dopamine D1-receptor levels (as indicated by [125I]SCH-23982 binding) and mRNA expression were measured using receptor autoradiographic and in situ hybridization histochemical techniques. [125I]NCQ-298 binding to D2-receptors was also measured as a positive control for the effects of Raclopride. SCH-23390 administration independently increased [125I]SCH-23982 binding in a region-dependent manner with the greatest increases occurring in the entopeduncular nucleus. SCH-23390 also increased D1-receptor mRNA expression in specific striatal subregions suggesting that increases in binding were related to changes in receptor synthesis. In addition, Raclopride independently enhanced D2 binding with comparable increases observed in extrastriatal regions and increases of a lesser magnitude in the striatum. These data show that the modulation of basal ganglia D1-receptor binding observed in animals treated with nonselective antagonists is due primarily to the blockade of D1-receptors. The differential enhancement in basal ganglia D1 binding observed after D1-receptor blockade may be due to anatomical or phenotypic heterogeneity within the population of striatal D1-receptor synthesizing neurons. Similarly, the differential enhancement in striatal and extrastriatal D2-receptor binding may be due to differences in the regulation of striatal and extrastriatal D2-receptor synthesizing neurons.
Asunto(s)
Ganglios Basales/metabolismo , Benzazepinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Autorradiografía , Benzazepinas/análogos & derivados , Benzazepinas/metabolismo , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Femenino , Radioisótopos de Yodo , Cinética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Racloprida , Ratas , Ratas Sprague-Dawley , Salicilamidas/farmacología , Sustancia Negra/metabolismoRESUMEN
Classical antipsychotics, such as fluphenazine, influence neurotransmission by blocking both dopamine D1- and D2-receptors which in turn results in widespread adaptive changes in the neurochemistry of the basal ganglia. The purpose of the present study was to determine the role of D1-receptors in mediating some of these neurochemical events, including changes in D1- and D2-receptor binding, and the expression of preproenkephalin and glutamic acid decarboxylase mRNAs. For these experiments, rats were given a depot injection of fluphenazine decanoate or injected twice daily for 21 days with the D1-receptor antagonist SCH-23390. An additional group received both fluphenazine and SCH-23390 and controls were given saline. Fluphenazine administration decreased D2-receptor binding throughout the basal ganglia while SCH-23390 was without effect. In contrast to the uniform reduction in D2-receptor binding, fluphenazine altered D1-receptor binding in a region-dependent manner. Region-dependent changes were also observed in animals given SCH-23390 which increased binding in the entopeduncular nucleus and posterior caudate-putamen without affecting other brain regions. Both fluphenazine and SCH-23390 significantly enhanced preproenkephalin and glutamic acid decarboxylase (GAD) mRNA expression in the anterior striatum. Fluphenazine also increased GAD mRNA levels in the entopeduncular nucleus. Together, these results indicate that the attenuation of D1-receptor-mediated neurotransmission modulates a number of clinically relevant neurochemical processes in the basal ganglia.
Asunto(s)
Ganglios Basales/fisiología , Flufenazina/farmacología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Transmisión Sináptica/efectos de los fármacos , Análisis de Varianza , Animales , Antipsicóticos/farmacología , Ganglios Basales/efectos de los fármacos , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Encefalinas/biosíntesis , Femenino , Glutamato Descarboxilasa/biosíntesis , Precursores de Proteínas/biosíntesis , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacosRESUMEN
Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.
Asunto(s)
Monoaminas Biogénicas/líquido cefalorraquídeo , Líquido Cefalorraquídeo/metabolismo , Dopamina/genética , Receptores Dopaminérgicos/genética , Tirosina 3-Monooxigenasa/genética , Adulto , Monoaminas Biogénicas/metabolismo , Femenino , Genotipo , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Trastornos Mentales/genética , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Persona de Mediana Edad , Polimorfismo Genético , Estaciones del AñoRESUMEN
In a series of studies tyrosine transport was investigated in patients with schizophrenia. Plasma amino acids competing with tyrosine for transport with the L-system were found to be elevated, and correlated negatively with homovanillic acid levels in the cerebrospinal fluid of the patients. The results were interpreted as a decrease in the transport of tyrosine to the brain leading to a reduced dopamine turnover. In in vitro studies with fibroblasts the transport capacity of tyrosine was found to be decreased (a lower Vmax value) in the patients. No changes in transport mechanism for the other neutral amino acids were found. The finding of a lower transport capacity in patients was replicated in a new sample in whom tyrosine transport also was determined in vivo with positron emission tomography. The in vivo studies demonstrated a decrease in the influx of tyrosine across the blood-brain barrier. Altogether the results were interpreted in support of the view of schizophrenia as a systemic disorder with a primary disturbance in cell membrane function.
Asunto(s)
Fibroblastos/metabolismo , Esquizofrenia/metabolismo , Tirosina/metabolismo , Aminoácidos/sangre , Transporte Biológico , Biopsia , Radioisótopos de Carbono , Femenino , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Indicadores y Reactivos , Masculino , Membranas/metabolismo , Esquizofrenia/fisiopatología , Tirosina/análisisAsunto(s)
Educación Médica Continua , Educación Médica , Médicos Mujeres , Prejuicio , Investigación , Femenino , Humanos , Masculino , Factores Sexuales , SueciaRESUMEN
SCH 39166 is the first selective D1 dopamine receptor antagonist developed for the treatment of schizophrenic patients. To examine potential antipsychotic effect, tolerability and safety, SCH 39166 was given orally to 17 acutely ill drug free schizophrenic patients (DSMIIIR) in an open 4-week study. Doses were escalated from 10 to 100 mg b.i.d. according to a fixed schedule over 17 days and remained at 100 mg b.i.d. for another 11 days. The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166. In the nine patients participating for more than 2 weeks, none had an apparent reduction of BPRS or CGI scores. Side effects were agitation, akathisia and emesis in single patients. After withdrawal of SCH 39166 of the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D1 dopamine receptor antagonism will produce antipsychotic effects in schizophrenia.
Asunto(s)
Benzazepinas/efectos adversos , Benzazepinas/farmacología , Benzazepinas/uso terapéutico , Escalas de Valoración Psiquiátrica Breve , Antagonistas de Dopamina/efectos adversos , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/uso terapéutico , Receptores de Dopamina D1/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The effect of the classical neuroleptic, fluphenazine, on dopamine D1-receptor binding was examined in different regions of the basal ganglia. Whereas exposure to fluphenazine for 18 months reduced [125I]SCH-23982 binding to D1-receptors in the caudate putamen, nucleus accumbens and olfactory tubercle, binding in the entopeduncular nucleus was enhanced after fluphenazine treatment. Competition studies indicated that the region-dependent changes in [125I]SCH-23982 binding after fluphenazine exposure were not due to differences in the affinity of fluphenazine or other dopamine ligands for D1-binding sites. These data suggest that in addition to modulating striatal function, classical neuroleptics may also alter neurotransmission in the basal ganglia by enhancing dopamine receptor binding in the entopeduncular nucleus.
Asunto(s)
Antipsicóticos/farmacología , Receptores de Dopamina D1/metabolismo , Animales , Autorradiografía , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Benzazepinas/análogos & derivados , Benzazepinas/farmacología , Unión Competitiva/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Femenino , Radioisótopos de Yodo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacosRESUMEN
The purpose of the following experiments was to describe some of the neurochemical changes that occur in the basal ganglia of rats exposed chronically to a classical neuroleptic, fluphenazine, and to relate these changes to extrapyramidal motor dysfunction. For these studies a combination of behavioural, receptor autoradiographic and in situ hybridization methods were employed. Preliminary pharmacological studies on GABA receptors showed that incubation in Tris-acetate rather than Tris-citrate buffer increased the number of binding sites labelled by [3H]muscimol by over 120% without affecting binding affinity or selectivity. The results of experiments with fluphenazine showed that treatment for six months increased the frequency of vacuous chewing movements compared to controls. In the striatum, changes in GABA transmission were observed in fluphenazine-treated rats with increases in glutamate decarboxylase mRNA levels in the caudate nucleus, dorsal shell and core of the accumbens and decreases in [3H]muscimol binding in the caudate and dorsal shell regions. These data suggest that fluphenazine treatment increased GABA transmission in specific subregions of the caudate and accumbens nuclei. In addition, glutamate decarboxylase mRNA levels were elevated in the entopeduncular nucleus of fluphenazine-treated animals. Autoradiographic analysis of excitatory amino acid binding showed that fluphenazine exposure decreased [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding in entopeduncular nucleus and in the ventrolateral thalamic nucleus and decreased [3H]dizocilpine maleate binding in the medial geniculate nucleus. These experiments show that in addition to altering GABA transmission, chronic neuroleptic exposure alters excitatory amino acid transmission in specific regions of the basal ganglia-thalamocortical motor system. The neuroleptic dependent increases in glutamate decarboxylase mRNA levels in the entopeduncular nucleus may reflect changes in neurotransmission in the indirect pathway connecting the major input and output nuclei of the basal ganglia. Changes in some of these brain regions may be related to the occurrence of extrapyramidal motor disturbances.