RESUMEN
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
Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.
Asunto(s)
Antipsicóticos/uso terapéutico , Encéfalo/metabolismo , Receptores Dopaminérgicos/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Antagonistas de Dopamina , Femenino , Haloperidol/farmacología , Haloperidol/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Nortriptilina/metabolismo , Nortriptilina/farmacología , Putamen/diagnóstico por imagen , Putamen/metabolismo , Radiografía , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/metabolismo , Sulpirida/farmacología , Sulpirida/uso terapéutico , Tomografía Computarizada de EmisiónRESUMEN
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
Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and [11C]raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.
Asunto(s)
Antipsicóticos/uso terapéutico , Ganglios Basales/metabolismo , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/metabolismo , Adulto , Ganglios Basales/diagnóstico por imagen , Radioisótopos de Carbono , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/metabolismo , Dopamina/fisiología , Femenino , Humanos , Masculino , Putamen/diagnóstico por imagen , Putamen/metabolismo , Racloprida , Receptores de Dopamina D2 , Salicilamidas/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Tomografía Computarizada de Emisión , Regulación hacia ArribaRESUMEN
Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.
Asunto(s)
Antipsicóticos/metabolismo , Enfermedades de los Ganglios Basales/inducido químicamente , Clozapina/metabolismo , Receptores Dopaminérgicos/metabolismo , Tomografía Computarizada de Emisión , Adolescente , Adulto , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/fisiopatología , Benzazepinas/metabolismo , Clozapina/efectos adversos , Clozapina/uso terapéutico , Antagonistas de Dopamina , Femenino , Humanos , Radioisótopos de Yodo/metabolismo , Masculino , Putamen/efectos de los fármacos , Putamen/metabolismo , Racloprida , Receptores Dopaminérgicos/efectos de los fármacos , Salicilamidas/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismoRESUMEN
The concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and glutamate were determined in cerebrospinal fluid (CSF) and serum in 10 healthy volunteers. The monoamine metabolites were measured by mass fragmentography and the glutamate by high-performance liquid chromatography. The level of glutamate in CSF was low (0.34 +/- 0.14 nmol/ml) in comparison with previously published values. The concentrations of monoamine metabolites in CSF were in close agreement with earlier findings. There were negative correlations between the concentrations of HVA (r = -0.82, p less than 0.01) and 5-HIAA (r = -0.77, p less than 0.01) and glutamate in CSF, but not in serum. The serum levels of HMPG and glutamate were negatively correlated (r = -0.95, p less than 0.001), but not the CSF levels. The HMPG levels in serum and CSF were positively correlated (r = 0.94, p less than 0.001), but not the HVA and the 5-HIAA levels. The serum and CSF levels of glutamate were positively correlated (r = 0.67, p less than 0.05). The results indicate relationships among the metabolism of dopamine, serotonin, and glutamate in the brain and between the metabolism of noradrenaline and glutamate in peripheral tissue.
Asunto(s)
Barrera Hematoencefálica , Glutamatos/líquido cefalorraquídeo , Glicoles/líquido cefalorraquídeo , Ácido Homovanílico/líquido cefalorraquídeo , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Adulto , Femenino , Ácido Glutámico , Humanos , Masculino , Valores de ReferenciaRESUMEN
The relationship between central D2-dopamine receptor occupancy and antipsychotic drug effects was examined in a double-blind study. Raclopride was the compound used to induce a selective occupancy of the D2-dopamine receptors. In addition, 11C-labeled raclopride was the radioligand used to measure occupancy by positron emission tomography (PET). Seventeen schizophrenic patients were randomly assigned to one of three parallel groups treated for 4 weeks with daily doses of 2, 6, or 12 mg of raclopride. D2-receptor occupancy was determined by PET at steady-state conditions in 13 patients who completed the study. A statistically significant relationship was demonstrated between antipsychotic effect and degree of D2-receptor occupancy (p < 0.05). Patients with extrapyramidal side effects had significantly higher D2-receptor occupancy than those without (p = 0.02). The finding of a relationship between selective occupancy of the D2-dopamine receptors and clinical effects in schizophrenic patients principally provides new support for the dopamine hypothesis of antipsychotic drug action.
Asunto(s)
Antipsicóticos/uso terapéutico , Encéfalo/diagnóstico por imagen , Receptores de Dopamina D2/efectos de los fármacos , Salicilamidas/uso terapéutico , Esquizofrenia/diagnóstico por imagen , Adulto , Antipsicóticos/efectos adversos , Antipsicóticos/sangre , Antagonistas de los Receptores de Dopamina D2 , Método Doble Ciego , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Racloprida , Salicilamidas/efectos adversos , Salicilamidas/sangre , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Tomografía Computarizada de EmisiónRESUMEN
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
In 66 physically and mentally healthy human subjects the total concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and dihydroxyphenyl acetic acid (DOPAC) in urine collected between midnight and 8 AM were analyzed by mass fragmentography. In the volunteers reporting the occurrence of psychiatric morbidity among relatives an increased variance in their MOPEG levels was found as compared to the volunteers without such a family history. In the male subjects with no family history of psychiatric disease there was a positive correlation between urine and cerebrospinal fluid levels of MOPEG. The urine levels of 5-HIAA, HVA, and DOPAC did not demonstrate any changes that could be related to psychopathology within the family. Changes in urine secretion of MOPEG indicate an altered metabolism of norepinephrine/MOPEG in some subjects with the occurrence of severe psychiatric disease within the family. MOPEG levels in urine may be a predictor of a family vulnerability for psychiatric morbidity in healthy subjects.
Asunto(s)
Trastornos Mentales/genética , Neurotransmisores/orina , Ácido 3,4-Dihidroxifenilacético/orina , Adolescente , Adulto , Femenino , Ácido Homovanílico/orina , Humanos , Ácido Hidroxiindolacético/orina , Masculino , Trastornos Mentales/orina , Metoxihidroxifenilglicol/orina , RiesgoRESUMEN
Human fetal brain tissue was obtained from first-trimester elective abortions of two women who also had schizophrenia. Portions of the embryonic hippocampus or cerebral cortex were transplanted into the anterior eye chamber of immunologically compromised athymic nude rats. In this environment, embryonic brain tissue derived from normal women generally continues organotypic growth and development for many months. Although initial survival after transplantation was normal, the tissue derived from schizophrenic women manifested less robust growth. However, cells in the transplants showed typical neuronal differentiation, with development of different neuronal types, such as pyramidal cells, granule cells, and gamma-aminobutyric acid (GABA)-containing interneurons. Rhythmic electrical activity was also observed, indicative of some local synaptic organization. The presence of messenger RNA (mRNA) for brain-derived neuronotrophic factor (BDNF) was observed using in situ hybridization. The reason for the decreased rate of growth of these transplants remains unknown and the significance of the finding cannot be assessed from only two fetuses. However, these preliminary findings suggest that fetal transplants may be a useful model system for the detection of developmental pathogenic processes in the expression and transmission of schizophrenia.
Asunto(s)
Trasplante de Tejido Encefálico/fisiología , Corteza Cerebral/trasplante , Trasplante de Tejido Fetal/fisiología , Hipocampo/trasplante , Esquizofrenia/genética , Psicología del Esquizofrénico , Adulto , Animales , Factor Neurotrófico Derivado del Encéfalo , Corteza Cerebral/fisiopatología , Femenino , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/fisiología , Supervivencia de Injerto/genética , Supervivencia de Injerto/fisiología , Hipocampo/fisiopatología , Humanos , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Neuronas/fisiología , Hibridación de Ácido Nucleico , Embarazo , Ratas , Ratas Desnudas , Esquizofrenia/fisiopatología , Transmisión Sináptica/genética , Transmisión Sináptica/fisiología , Trasplante Heterólogo , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/fisiología , Ácido gamma-Aminobutírico/genética , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
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
Regional CMRglc was measured in seven healthy volunteers with positron emission tomography using [1-11C]D-glucose. Regional CBF was measured using [11C]fluoromethane. The arteriovenous differences of unlabeled glucose and oxygen together with 11C metabolites were also measured. In addition to the loss of [11C]CO2, a loss of acidic 11C metabolites was also detected. A three-compartment model was applied to the tracer data in the time interval 0-24 min. After correction for the loss of 11C metabolites, the tracer method gave an average CMRglc of 26.4 +/- 1.9 (SD) mumol/100 g/min, close to the value obtained with the Fick principle. After correction for the loss of [11C]CO2 only, the tracer method gave 23.6 +/- 2.1 mumol/100 g/min, compatible with (1/6) CMRO2, obtained with the Fick principle. These results and the time course of the loss of acidic 11C metabolites are consistent with the presence of nonoxidative metabolism of glucose that causes an early loss of mainly [11C]lactate after a bolus injection of the tracer. This implies that [1-11C]D-glucose measures the rate of glucose oxidation rather than the total CMRglc. The experiments using [1-11C]D-glucose were compared to five analogous experiments using [U-11C]D-glucose together with [15O]H2O as a flow tracer. After correction for the loss of [11C]CO2, the two glucose tracers gave similar global values of CMRglc and other parameters associated with glucose utilization, but with labeling in the carbon-1 position, the loss of [11C]CO2 was substantially delayed and the contrast between gray and white matter was improved.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Encéfalo/metabolismo , Glucosa/metabolismo , Tomografía Computarizada de Emisión , Algoritmos , Dióxido de Carbono/metabolismo , Radioisótopos de Carbono , HumanosRESUMEN
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.
Asunto(s)
Antipsicóticos/farmacología , Encéfalo/fisiología , Aminoácidos Excitadores/fisiología , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/fisiología , Animales , Autorradiografía , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiología , Enfermedades de los Ganglios Basales/fisiopatología , Encéfalo/efectos de los fármacos , Maleato de Dizocilpina/metabolismo , Femenino , Flufenazina/análogos & derivados , Flufenazina/farmacología , Glutamato Descarboxilasa/biosíntesis , Hibridación in Situ , Muscimol/farmacología , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
Catecholamine nerve terminals in the rat median eminence have been studied using the fluorescence histochemical technique of Falck and Hillarp in combination with quantitative microfluorimetry. The catecholamine fluorescence intensities recorded from various parts of the median eminence were all found to be within the linear part of the dopamine or noradrenaline concentration-fluorescence relationship as studied in an agar-albumin model system. The catecholamine fluorescence was also found to disappear with time in an exponential manner following tyrosine hydroxylase inhibition produced by alpha-methyl-p-tyrosine methylester (H44/68). Similar results were obtained when measuring the dopamine decline by mass fragmentography in the median eminence after H44/68 treatment. These results and analysis of fluorescence frequency histograms strongly indicate that the catecholamine fluorescence values recorded are proportional to the catecholamine concentration. It is concluded that the microfluorimetric technique used is a reliable method for catecholamine quantitation in discrete nerve terminal areas of the median eminence. The main advantages of the technique are that a high sensitivity and quantitative data on the transmitter content can be obtained in strict relation to the neuroanatomy. Measurement of the catecholamine fluorescence disappearance after H44/68 was used to evaluate catecholamine turnover during various endocrine states. The results showed that two dopamine systems with different transmitter turnover may be distinguished. Tuberinfundibular dopamine neurons projecting to the lateral palisade zone were thus shown to have a slower turnover than those projecting medially to the capillary loops. No definite changes in catecholamine turnover were observed after adrenalectomy and castration in the male, although there was a tendency toward increased noradrenaline turnover in both states. During pregnancy an increase in noradrenaline as well as dopamine turnover was noted. The present results therefore give further evidence for the view that catecholamine nerve terminals in the median eminence may participate in the regulation of gonadotrophin secretion.
Asunto(s)
Sistema Hipotálamo-Hipofisario/metabolismo , Eminencia Media/metabolismo , Norepinefrina/metabolismo , Adrenalectomía , Análisis de Varianza , Animales , Castración , Femenino , Masculino , Eminencia Media/citología , Eminencia Media/ultraestructura , Microscopía Fluorescente/métodos , Embarazo , Ratas , Factores Sexuales , Espectrometría de FluorescenciaRESUMEN
An alteration of dopaminergic transmission in the brain has been proposed for schizophrenia. To explore this, the rate constant for the intransport of L-tyrosine across the blood-brain barrier in healthy controls and in patients with schizophrenia (DSM-III-R) was determined with PET and L-[1-11C] tyrosine as the tracer. Kinetics for tyrosine transport were determined according to a two-compartment model using radioactivity data of arterial blood and brain tissue sampled between 1 and 3.5 min after a bolus injection of L-[1-11C] tyrosine. Radioactivity was measured every second in the blood and in 10-sec intervals in the brain tissue. In the normal controls the brain intransport rate constant for tyrosine was 0.052 ml/g/min with an influx rate of 2.97 nmol/g/min. The patients had a similar intransport rate constant (0.045 ml/g/min) but a lower influx rate of tyrosine 1.95 nmol/g/min (p less than 0.05). The patients' tyrosine concentrations in the blood were lower. For data sampled between 5 and 25 min, the net accumulation rate of tyrosine into the brain was 0.015 ml/g/min in the controls which did not differ to the patients' rate. However, the net utilization of tyrosine was lower in the patients (0.672 nmol/g/min) than in the controls (0.883 nmol/g/min) despite similar tissue concentrations of tyrosine.
Asunto(s)
Encéfalo/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagen , Tomografía Computarizada de Emisión , Tirosina , Adulto , Transporte Biológico , Barrera Hematoencefálica/efectos de los fármacos , Radioisótopos de Carbono , Humanos , Masculino , Esquizofrenia/metabolismo , Tirosina/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
Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18-42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (400, 800 or 1200 mg) according to a double dummy blind randomized administration schedule. The psychopathology of the patients was rated by the Comprehensive Psychopathological Rating Scale (CPRS) and the Nurse's Observation Scale for Inpatient Evaluation (NOSIE). The monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before and once a week during sulpiride treatment. There were no significant correlations between the CPRS or the NOSIE morbidity scores and the biochemical measures before drug treatment. HVA levels were not correlated to rating scores during treatment, but after 6 weeks HVA had decreased significantly in the patients with a good response but not in the patients with a poor response. A negative relationship between 5-HIAA levels and depressive and negative symptoms was found. Non-responders according to the subscale for depression had low 5-HIAA levels throughout the treatment. An increase of tryptophan was correlated to improvement in the early part of treatment. High levels of glutamate or glutamine were found in non-responders before treatment. During treatment an increase of the glutamate level was correlated to improvement. Low levels of glutamine were related to improvement according to global and NOSIE (total) rating scores. Peripheral biochemical measures may be a valuable tool in the study of pathophysiological mechanisms and treatment effects in patients with schizophrenia.
Asunto(s)
Aminoácidos/sangre , Monoaminas Biogénicas/sangre , Esquizofrenia/sangre , Sulpirida/uso terapéutico , Adolescente , Adulto , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Sulpirida/efectos adversosRESUMEN
Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18-42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (starting with 400, 800 or 1200 mg) according to a double blind randomized administration schedule. The monoamine metabolites (MAM) homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before treatment and once a week during treatment. There were no significant differences between healthy controls and schizophrenic patients in serum levels of monoamine metabolites and amino acids before treatment. There was no dose-response effect of sulpiride on serum levels of the monoamine metabolites or the amino acids. The results are therefore based on the whole group of patients. During treatment the HMPG levels were reduced at all points in time. The serum level of HVA was significantly reduced after 6 weeks. The 5-HIAA and the amino acid levels were not changed during treatment. There were no significant correlations among the monoamine metabolites before treatment. During treatment, however, significant correlations were found among MAM and amino acids. Since the biochemical findings during the treatment were not related to the dose or the concentration of sulpiride the results may be related to secondary biochemical effects of sulpiride and/or to changes in the clinical state following treatment.
Asunto(s)
Aminoácidos/sangre , Monoaminas Biogénicas/sangre , Esquizofrenia/sangre , Sulpirida/uso terapéutico , Adolescente , Adulto , Femenino , Glutamatos/sangre , Glutamatos/líquido cefalorraquídeo , Glutamina/sangre , Ácido Homovanílico/sangre , Humanos , Ácido Hidroxiindolacético/sangre , Masculino , Meglutol/líquido cefalorraquídeo , Esquizofrenia/líquido cefalorraquídeo , Esquizofrenia/tratamiento farmacológico , Sulpirida/sangre , Triptófano/sangre , Tirosina/sangreRESUMEN
Schizophrenic patients were treated with fixed doses of sulpiride (800 mg/day) or chlorpromazine (CPZ) (400 mg/day) during a period of 8 weeks using a double-blind design. There were 25 patients in each group and all of them fulfilled the Research Diagnostic Criteria (RDC) for schizophrenia. Autistic and psychotic symptoms were rated with subscales developed from the Comprehensive Psychopathological Rating Scale (CPRS). Autistic symptoms were also rated with a subscale of the Nurse's Observation Scale for Inpatient Evaluation (NOSIE). Sulpiride was superior to CPZ in reducing the autistic symptoms. Patients with low concentrations of sulpiride in serum had a better recovery rate from autistic symptoms than those with high concentrations. Both drugs reduced positive psychotic symptoms to the same degree.
Asunto(s)
Trastorno Autístico/tratamiento farmacológico , Clorpromazina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Sulpirida/uso terapéutico , Adolescente , Adulto , Trastorno Autístico/psicología , Conducta/efectos de los fármacos , Clorpromazina/efectos adversos , Clorpromazina/sangre , Ensayos Clínicos como Asunto , Método Doble Ciego , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Trastornos Psicóticos/psicología , Esquizofrenia/diagnóstico , Sulpirida/efectos adversos , Sulpirida/sangre , Factores de TiempoRESUMEN
Levels of monoamine metabolites in three different regions of the rat brain were determined following treatment with piracetam (0.5 and 5 g/kg, i.p.). The concentration of prolactin in serum was also measured. Piracetam, at 5 g/kg, increased the levels of dihydroxyphenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, whereas 5-hydroxyindoleacetic acid was unaffected. The drug also increased prolactin concentrations in serum. The level of dopamine was unchanged in the olfactory tubercle and the striatum. These effects are different from those obtained with amphetamine-like drugs. The results would seem to indicate that piracetam accelerates brain catecholamine (CA) turnover via a blockade of CA receptors, as suggested for neuroleptic drugs. This effect could be responsible for the therapeutic action of piracetam on psychotic symptoms in psycho-organic disorders of old age. A blockade of brain CA receptors by piracetam is not compatible with facilitated learning, which seems to be mediated via other neuron systems than CA pathways.