RESUMEN

The continuous intra-cortical infusion of a glia toxin, fluorocitrate, at the concentration of 1 mM caused a decrease in the cortical extracellular contents of an intrinsic coagonist for the N-methyl-D-aspartate (NMDA) type glutamate receptor, D-serine, by peaking at 40 min by -25% but produced an increase in those of glycine and L-serine. The attenuated glial activity by fluorocitrate was verified by a marked reduction in the extracellular glutamine contents. The present findings suggest that a group of glial cells such as a population of the protoplasmic astrocytes could, at least in part, participate differently in the regulation of the extracellular release of D-serine and another NMDA coagonist glycine in the medial frontal cortex of the rat.

Asunto(s)

Encéfalo/metabolismo , Líquido Extracelular/química , Líquido Extracelular/metabolismo , Neuroglía/metabolismo , Serina/metabolismo , Animales , Área Bajo la Curva , Encéfalo/efectos de los fármacos , Citratos/toxicidad , Glutamina/metabolismo , Masculino , Microdiálisis , Neuroglía/efectos de los fármacos , Ratas , Ratas Wistar , Serina/efectos de los fármacos

RESUMEN

An anxiogenic or a pharmacological stressor, N-methyl-beta-carboline-3-carboxamide (FG-7142), (20 mg/kg, intraperitoneally injected) induced a dense nuclear c-Fos-like immunoreactivity in the pyriform cortex, cingulate and retrosplenial cortex, layers II-VI of the neocortex, lateral habenula, lateral septum, paraventricular nucleus of the thalamus, striatum, central and medial nucleus of the amygdala, but a sparse c-Fos immunostaining in the hippocampus and layer I of the neocortex in the forebrain of 56-day-old rats. Among these regions, the 8-day-old rats expressed much fewer c-Fos-positive cells in the neocortex, lateral habenula, lateral septum and medial nucleus of the amygdala than the young adult rats following the FG-7142 injection. These differences in the regional distribution of a neuronal activity marker, c-Fos, could reflect the postnatal development of neuronal populations or neuron circuits involved in stress and/or emotional response in the forebrain.

Asunto(s)

Envejecimiento/metabolismo , Carbolinas/farmacología , Antagonistas del GABA/farmacología , Prosencéfalo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Animales , Ansiedad/metabolismo , Inmunohistoquímica , Masculino , Prosencéfalo/crecimiento & desarrollo , Prosencéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Estrés Psicológico/metabolismo

RESUMEN

In neurons, pituitary adenyl cyclase activating peptide (PACAP) stimulates signaling cascades, involving cAMP and calcium. PACAP appears to play a role in up-regulation of tyrosine hydroxylase and dopamine beta-hydroxylase via protein kinase C and/or protein kinase A. Furthermore, the PACAP gene (ADCYAP1) is located in chromosome 18p11, where linkage of bipolar disorders and schizophrenia has been reported. In this study, we scanned the coding region of the PACAP gene for mutations in 24 Japanese patients with schizophrenia and 24 Japanese patients with bipolar disorders. No variant in the coding region was found. One polymorphism, INV3-37A/T, in the third intron was detected. Case-control comparisons revealed no significant association between this polymorphism and schizophrenia or bipolar disorders. This study did not provide evidence for the contribution of the PACAP gene to the etiology of schizophrenia or bipolar disorders in the Japanese population.

Asunto(s)

Trastorno Bipolar/genética , Cromosomas Humanos Par 18/genética , Neuropéptidos/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Polimorfismo Genético/genética

RESUMEN

Tyrosine hydroxylase (TH) is the rate limiting enzyme in the synthesis of dopamine and norepinephrine. A polymorphic repeat of the tetranucleotide (TCAT) in the first intron of the TH gene may behave as a regulatory element for the gene expression. Allelic fragments of the tandem repeat were typed by a PCR-based process with a pair of primers specific for the polymorphic sequence. The association between the polymorphism and schizophrenia was examined in a Japanese sample. There was a statistically significant association between the polymorphism and schizophrenia in females (chi2 = 26.018, p = 0.010), but not in males (chi2 = 15.995, p = 0.305). The genotype heterozygous for the TH9 and TH6 was significantly decreased in female schizophrenics (chi2 = 5.125, p = 0.0236). These results suggest that TH could be considered as a minor gene contributing to the susceptibility of Japanese female schizophrenia.

Asunto(s)

Repeticiones de Microsatélite , Esquizofrenia/genética , Tirosina 3-Monooxigenasa/genética , Adulto , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Intrones/genética , Japón , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Esquizofrenia/enzimología , Factores Sexuales

RESUMEN

L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.

Asunto(s)

Glicoproteínas de Membrana/genética , Moléculas de Adhesión de Célula Nerviosa/genética , Esquizofrenia/genética , Adulto , Secuencia de Bases , Femenino , Orden Génico , Pruebas Genéticas , Genotipo , Humanos , Japón , Complejo de Antígeno L1 de Leucocito , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple

RESUMEN

The benzodiazepine receptor (peripheral) (BZRP) plays an important role in the steroid syntheses of the adrenal glands and brain, which is possibly involved in the pathophysiology of mood disorders. We evaluated an association study between two missense variations of the BZRP gene and mood disorders in a Japanese sample. However, no statistically significant associations with either bipolar disorders or depressive disorders were observed in the allele frequencies, genotype counts, or haplotype distributions for the two variations, although the present sample size had a moderate power (0.46-0.86). These results do not suggest that the BZRP gene plays a role in the genetic predisposition of affective disorders.

Asunto(s)

Trastornos del Humor/genética , Mutación Missense , Receptores de GABA-A/genética , Adulto , Anciano , Depresión/genética , Exones , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Japón , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Polimorfismo Genético , Polimorfismo de Nucleótido Simple

RESUMEN

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.

Asunto(s)

Cromosomas Humanos Par 18 , Monoéster Fosfórico Hidrolasas/genética , Esquizofrenia/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Haplotipos , Humanos , Japón , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Trastornos del Humor/genética , Mutación Missense , Polimorfismo Genético , Factores de Riesgo , Esquizofrenia/etnología

RESUMEN

Abnormalities in neural transmission of dopamine play an important role in development of schizophrenia. Dopamine 1 (D1)-like receptors in 16 areas of the cerebral cortex were measured in the postmortem brains of 13 schizophrenics and 10 controls, using [3H]SCH23390 as a ligand for receptor binding. The specific [3H]SCH23390 bindings were statistically significantly increased in the medial and inferior cortex (Brodmann Area (BA) 20 & 21) and superior parietal cortex (BA 7) of schizophrenic patients, compared to those of the controls. The increases were also marked in the cerebral cortices of off-drug cases of patients with schizophrenia, who had not received antipsychotic drugs for more than 40 days before death. These results suggest that there are changes in dopaminergic transmission through the D1 receptors in the parieto-temporal cortex of schizophrenia, and that the altered functions are involved in the pathophysiology of the disease.

Asunto(s)

Benzazepinas/metabolismo , Corteza Cerebral/metabolismo , Antagonistas de Dopamina/metabolismo , Receptores de Dopamina D1/metabolismo , Esquizofrenia/metabolismo , Transmisión Sináptica/fisiología , Regulación hacia Arriba/fisiología , Adulto , Factores de Edad , Anciano , Sitios de Unión/fisiología , Corteza Cerebral/fisiopatología , Dopamina/metabolismo , Movimientos Oculares/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas/metabolismo , Lóbulo Parietal/metabolismo , Lóbulo Parietal/fisiopatología , Ensayo de Unión Radioligante , Receptores de Dopamina D1/efectos de los fármacos , Esquizofrenia/fisiopatología , Lóbulo Temporal/metabolismo , Lóbulo Temporal/fisiopatología , Tritio/metabolismo

RESUMEN

We examined the effects of neonatal treatment with MK-801 on 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shaking as well as [(3)H]ketanserin binding in adult rats. Neonatal rats were injected with MK-801 (0.25 mg/kg, s.c., twice daily) or with saline from postnatal days (PND) 7-18. At PND 60, a statistically significant increase in the frequency of head shaking induced by DOI (1.0 mg/kg, s.c.) was observed in the rats neonatally treated with MK-801, compared to saline-treated rats, without any change in the specific [(3)H]ketanserin binding in the frontal cortex. These results suggest that repeated NMDA receptor blockades during the critical period of brain development produce a long lasting hyper-responsiveness in the 5-HT(2A) receptor-mediated behavior, interfering with the development of neural circuits related to the behavior.

Asunto(s)

Anfetaminas , Animales Recién Nacidos/fisiología , Maleato de Dizocilpina/farmacología , Discinesia Inducida por Medicamentos/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Cabeza/fisiopatología , Agonistas de Receptores de Serotonina , Animales , Sinergismo Farmacológico , Ketanserina/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/metabolismo

RESUMEN

We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6 (dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22-23, which overlaps one of the reported bipolar disorder susceptibility loci. Because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. We performed association analysis using a T>G polymorphism that gives rise to a missense mutation (Leu114Val). No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 132) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs).

Asunto(s)

Trastorno Bipolar/genética , Cromosomas Humanos Par 12 , Pruebas Genéticas/métodos , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas/genética , Adulto , Anciano , Alelos , Análisis Mutacional de ADN/métodos , Trastorno Depresivo/genética , Fosfatasa 6 de Especificidad Dual , Femenino , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Mutación Missense , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción , Espectrometría de Fluorescencia

RESUMEN

We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6 (dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22-23, which overlaps one of the reported bipolar disorder susceptibility loci. Because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. We performed association analysis using a T>G polymorphism that gives rise to a missense mutation (Leu114Val). No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 132) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs). Molecular Psychiatry (2000) 5, 489-494.

RESUMEN

The benzodiazepine receptor (peripheral) (BZRP) mainly localized on glial cells plays a role in neurosteroid synthesis, and increases with glial proliferation. We have recently reported a significant decrease in the density of BZRP labeled by [3H] PK 11195 in the postmortem brain of chronic schizophrenics, suggesting that dysfunctions of the BZRP are involved in the pathophysiology of schizophrenia. We screened 11 patients with schizophrenia and 10 controls, which were used in a previous postmortem study, for their genomic sequences of the BZRP gene in order to find DNA sequence variations. One novel missense polymorphism (His162Arg) and another previously reported missense mutation (Ala147Thr) were detected. An association study of the identified variations was then performed in an extended Japanese sample of 304 schizophrenic patients and 369 controls. While there was an increased tendency in the frequency of the 162Arg allele of schizophrenics compared to that of the controls (p = 0.0603), no statistically significant association with schizophrenia was observed in the Ala147Thr allele (p = 0.1016). These results do not suggest that the two missense polymorphisms play a major role in the genetic predisposition of schizophrenia in the Japanese sample.

Asunto(s)

Exones/genética , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de GABA-A/genética , Esquizofrenia/genética , Adulto , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Método de Montecarlo , Análisis de Secuencia de ADN

RESUMEN

Several antipsychotic agents such as haloperidol and rimcazole are known to bind to sigma receptors with high affinity, and evidence for a potential link between sigma receptors and the etiology of schizophrenia has been reported. The present study was conducted to systematically search for nucleotide variants of the type 1 sigma receptor gene in 48 schizophrenics. Two polymorphisms were found: GC-241-240TT in the 5' flanking region and Gln2Pro. These two polymorphisms were in nearly complete linkage disequilibrium with each other. The Pro2 variant of the Gln2Pro polymorphism changes the endoplasmic reticulum retention signal motif. These polymorphisms were examined in an extended sample of schizophrenics (n = 308) and controls (n = 433) and a significant association between the presence of the TT/Pro2 haplotype and schizophrenia was observed (odds ratio = 1.27, P = 0.04).

Asunto(s)

Ligamiento Genético , Polimorfismo Genético/genética , Receptores sigma/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cartilla de ADN , Femenino , Frecuencia de los Genes , Glutamina/genética , Humanos , Japón , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa , Prolina/genética

RESUMEN

We measured adenosine 2a receptors in basal ganglia of 13 schizophrenics and 10 controls, using [3H] CGS21680 as a ligand for the receptor binding assay. There was a significant increase in the specific [3H] CGS21680 binding in the putamen and caudate, but not in the globus pallidus of externa, of the schizophrenic patients, compared to those of controls. These results provide evidence suggesting that adenosine 2a receptors play a role in the pathophysiology of schizophrenia.

Asunto(s)

Adenosina/análogos & derivados , Antihipertensivos/farmacología , Cuerpo Estriado/química , Fenetilaminas/farmacología , Receptores Adrenérgicos alfa 2/análisis , Esquizofrenia/metabolismo , Adenosina/metabolismo , Adenosina/farmacología , Adulto , Anciano , Antihipertensivos/metabolismo , Química Encefálica/fisiología , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenetilaminas/metabolismo , Ensayo de Unión Radioligante , Receptores Adrenérgicos alfa 2/metabolismo , Tritio

RESUMEN

Serotonergic systems were investigated in the frontal cortex of rats with thioacetamide (TAA)-induced acute hepatic encephalopathy (HE). Extracellular basal levels of 5-HT showed no difference between control and HE animals, whereas the levels of 5-HIAA were significantly increased in HE rats. Unlike basal levels, high K+-evoked 5-HT release was significantly higher in HE rats than controls. Bmax of (+/-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I] DOI) binding, mainly labeling postsynaptic 5-HT2A receptors, was significantly decreased without any change in Kd in HE rats. These results suggest that there is no change in basal 5-HT release in the cortex of rats with TAA-induced HE despite the increase in intraneuronal 5-HT metabolism and in the size of releasable 5-HT pool, and that serotonergic neurotransmission via 5-HT2A receptor is altered in the brain area of rats with HE.

Asunto(s)

Lóbulo Frontal/metabolismo , Encefalopatía Hepática/metabolismo , Potasio/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Enfermedad Aguda , Anfetaminas/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Espacio Extracelular/metabolismo , Lóbulo Frontal/ultraestructura , Encefalopatía Hepática/inducido químicamente , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2C , Agonistas de Receptores de Serotonina/metabolismo , Sinapsis/metabolismo , Tioacetamida/toxicidad , Triptófano/metabolismo

RESUMEN

We measured the peripheral-type benzodiazepine receptors (PBRs), a marker of gliosis, in 26 brain areas (cerebral cortex, thalamus and extrapyramidal system) of the postmortem brains of 13 chronic schizophrenics and 10 controls, using [3H] PK 11195 as a ligand for the receptor assay. The specific [3H] PK 11195 binding was significantly decreased in three brain areas (superior parietal cortex, primary visual area and putamen) of schizophrenics, although there were no changes in the binding in the other brain areas. Scatchard analysis revealed that there were decreases in both the Bmax and Kd of [3H] PK 11195 binding in the brain areas. These results were almost in accordance with a number of neuropathological studies reporting that there was no change or reduction in glial cells in the brain regions of schizophrenics and suggested that the decreased density of PBRs in the brain may be involved in the pathophysiology of schizophrenia, associated with reduced production of neurosteroids coupled to PBRs.

Asunto(s)

Química Encefálica/fisiología , Sistema Nervioso Periférico/metabolismo , Receptores de GABA-A/metabolismo , Esquizofrenia/metabolismo , Adulto , Anciano , Encéfalo/patología , Enfermedad Crónica , Femenino , Humanos , Isoquinolinas , Cinética , Masculino , Persona de Mediana Edad , Sistema Nervioso Periférico/patología , Esquizofrenia/patología

RESUMEN

We examined the postnatal development of peripheral-type benzodiazepine receptors (PBRs), labelled with [3H]PK 11195, in rat brain and peripheral tissues. Specific [3H]PK 11195 binding exhibited a heterogeneous patterns of postnatal development in the rat: three patterns of increase, decrease and no change. Hence, the density of the PBRs can be independently regulated in each tissue during postnatal development, and the postnatal alterations in the density might be parallel with the functional activities coupled to the receptors.

Asunto(s)

Química Encefálica , Encéfalo/crecimiento & desarrollo , Receptores de GABA-A/biosíntesis , Glándulas Suprarrenales/química , Glándulas Suprarrenales/crecimiento & desarrollo , Factores de Edad , Animales , Femenino , Corazón/crecimiento & desarrollo , Isoquinolinas/metabolismo , Isoquinolinas/farmacología , Riñón/química , Riñón/crecimiento & desarrollo , Hígado/química , Hígado/crecimiento & desarrollo , Pulmón/química , Pulmón/crecimiento & desarrollo , Masculino , Miocardio/química , Embarazo , Ratas , Ratas Wistar , Receptores de GABA-A/análisis , Receptores de GABA-A/metabolismo , Bazo/química , Bazo/crecimiento & desarrollo , Testículo/química , Testículo/crecimiento & desarrollo , Tritio

Asunto(s)

Receptores de Glutamato/fisiología , Esquizofrenia/fisiopatología , Humanos

RESUMEN

We have measured the concentrations of glycine and its potential precursors, serine and threonine, in 20 areas of the postmortem brains of chronic schizophrenics and controls using high-performance liquid chromatography by pre-column derivatization with dimethyl-amino-azobenzene sulphonyl chloride. The regional distribution pattern of glycine in the postmortem brains with and without the disease was more similar to that of serine (r = 0.874, P < 0.0001) than to that of threonine (r = 0.476, P < 0.01). A multiple regression analysis with regressor variables including diagnosis, age at death and interval between death and freezing revealed that there is a significant difference between schizophrenics and controls in the contents of these amino acids in a number of brain areas. The level of glycine in the orbitofrontal cortex of schizophrenics was found to be significantly increased in schizophrenics, with a tendency to an increase in that of serine. The increase in glycine was also significantly high in the off-drug group of schizophrenics who had not taken antipsychotics more than 40 days before death. Prominent decreases in both glycine and serine were observed in the somesthetic cortex of the on-drug schizophrenics. Serine was found to be significantly decreased in the putamen of the off-drug schizophrenics. A marked decrease in threonine was also observed in the supramarginal cortex and posterior portion of the lateral occipitotemporal cortex of the off-drug group of schizophrenics and in the putamen of all schizophrenics. The highly similar distribution pattern of glycine and serine in the postmortem brains supports the close coupling of synthesis and metabolism between these chemicals in human brains. The increased content of glycine in the orbitofrontal cortex, the reduced level of serine in the putamen and the decrease in threonine in the cerebral cortices, which were prominent in the off-drug schizophrenics, may be involved in the pathophysiology of schizophrenia.

Asunto(s)

Química Encefálica/fisiología , Glicina/metabolismo , Esquizofrenia/metabolismo , Adulto , Anciano , Cromatografía Líquida de Alta Presión , Enfermedad Crónica , Femenino , Humanos , Indicadores y Reactivos , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Serina/metabolismo , Treonina/metabolismo , p-Dimetilaminoazobenceno

RESUMEN

The effects of chronic treatment with haloperidol on [3H]PK 11195 binding and labelling of the peripheral-type benzodiazepine receptor (PBR) in the rat brain and peripheral tissues were investigated using an in vitro receptor binding technique. The intraperitoneal injection with haloperidol (0.3 or 1.0 mg/kg) for 21 days produced a significant increase in the specific [3H]PK 11195 binding only in the olfactory bulb, but not in the other brain areas or peripheral tissues, while single or subchronic (4 days or 7 days) administration with the drug (0.3 mg/kg, i.p.) failed to increase the binding in the olfactory bulb. Scatchard analysis revealed a significant increase in the maximum number of [3H]PK 11195 binding sites in the olfactory bulb after chronic treatment with haloperidol, showing no change in the affinity of the binding. These results suggest that there is an interaction between PBR and the pharmacological actions of haloperidol in the brain area, and that some compensatory mechanism may be involved in the PBR changes.

Asunto(s)

Antipsicóticos/farmacología , Encéfalo/metabolismo , Haloperidol/farmacología , Isoquinolinas/farmacocinética , Animales , Antipsicóticos/administración & dosificación , Encéfalo/efectos de los fármacos , Antagonistas de Receptores de GABA-A , Haloperidol/administración & dosificación , Técnicas In Vitro , Inyecciones Intraperitoneales , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Ratas , Ratas Wistar