The brain metabolic patterns of clozapine- and fluphenazine-treated female patients with schizophrenia: evidence of a sex effect. (1/96)

The regional cerebral glucose metabolic rates of clozapine-treated and fluphenazine-treated women with schizophrenia and normal controls were obtained by positron emission tomography (PET) using [18F]-2-fluoro-2-deoxy-D-glucose (FDG) as the tracer. The regional metabolic patterns were compared to each other and to the changes previously observed in men. In women, as in men, both clozapine- and fluphenazine-treatment were associated with lower metabolism in the superior prefrontal cortex and higher metabolism in the medial temporal lobe. In both men and women, clozapine treatment led to a greater lowering of inferior prefrontal cortex activity than fluphenazine, which was statistically significant in the larger male cohort. Fluphenazine led to higher metabolic rates in the lateral temporal lobe than clozapine did, but the differences between the two neuroleptics were not statistically significant in either group. The greatest differences in the female as compared to the male responses to fluphenazine and clozapine were in the cingulate and striatum. As compared to controls, the cingulate metabolic rates of women were reduced by 9.1% and 11.4% on clozapine and fluphenazine, respectively; whereas, men have a statistically nonsignificant reduction of 0.1% with clozapine and a 3.2% increase with fluphenazine. In men, fluphenazine was associated with a much greater elevation in basal ganglia metabolic rates than was clozapine, 23.5% as compared to 3.75%; whereas, in women, basal ganglia metabolic rates are nearly equally increased by fluphenazine (21.6%) and clozapine (15.1%).  (+info)

Chronic effect of antidopaminergic drugs or estrogen on male wistar rat lactotrophs and somatotrophs. (2/96)

The aim of the present study was to evaluate the effect of antidopaminergic agents on the somatotrophs in the presence of hyperprolactinemia. Adult male Wistar rats were divided into 6 groups: a control group and five groups chronically treated (60 days) with haloperidol, fluphenazine, sulpiride, metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by immunohistochemistry and the data are reported as percent of total anterior pituitary cells counted. The drugs significantly increased the percentage of lactotrophs: control (mean +/- SD) 21.3 +/- 4.4, haloperidol 27.8 +/- 2.2, fluphenazine 34.5 +/- 3.6, sulpiride 32.7 +/- 3.5, metoclopramide 33.4 +/- 5.5 and estrogen 42.4 +/- 2.8. A significant reduction in somatotrophs was observed in animals treated with haloperidol (23.1 +/- 3.0), fluphenazine (22.1 +/- 1.1) and metoclopramide (24.2 +/- 3.0) compared to control (27.3 +/- 3.8), whereas no difference was observed in the groups treated with sulpiride (25.0 +/- 2.2) and estrogen (27.1 +/- 2.8). In the groups in which a reduction occurred, this may have simply been due to dilution, secondary to lactotroph hyperplasia. In view of the duplication of the percentage of prolactin-secreting cells, when estrogen was applied, the absence of a reduction in the percent of somatotrophs suggests a replication effect on this cell population. These data provide additional information about the direct or indirect effect of drugs which, in addition to interfering with the dopaminergic system, may act on other pituitary cells as well as on the lactotrophs.  (+info)

Carbachol-stimulated transactivation of epidermal growth factor receptor and mitogen-activated protein kinase in T(84) cells is mediated by intracellular ca(2+), PYK-2, and p60(src). (3/96)

Ca(2+)-dependent agonists, such as carbachol (CCh), stimulate epidermal growth factor receptor (EGFR) transactivation and mitogen-activated protein kinase activation in T(84) intestinal epithelial cells. This pathway constitutes an antisecretory mechanism by which CCh-stimulated chloride secretion is limited. Here, we investigated mechanisms underlying CCh-stimulated epidermal growth factor receptor (EGFR) transactivation. Thapsigargin (TG, 2 microM) stimulated EGFR and extracellular signal-regulated kinase (ERK) phosphorylation in T(84) cells. Inhibition of either EGFR or ERK activation, with tyrphostin AG1478 (1 microM) and PD 98059 (20 microM), respectively, potentiated chloride secretory responses to TG, as measured by changes in short-circuit current (I(sc)) across T(84) cells. CCh (100 microM) stimulated tyrosine phosphorylation and association of the Ca(2+)-dependent tyrosine kinase, PYK-2, with the EGFR, which was inhibited by the Ca(2+) chelator, BAPTA (20 microM). The calmodulin inhibitor, fluphenazine (50 microM) inhibited CCh-stimulated PYK-2 association with the EGFR and phosphorylation of EGFR and ERK. CCh also induced tyrosine phosphorylation of p60(src) and association of p60(src) with both PYK-2 and the EGFR. The Src family kinase inhibitor, PP2 (20 nM-20 microM) attenuated CCh-stimulated EGFR and ERK phosphorylation and potentiated chloride secretory responses to CCh. We conclude that CCh-stimulated transactivation of the EGFR is mediated by a pathway involving elevations in intracellular Ca(2+), calmodulin, PYK-2, and p60(src). This pathway represents a mechanism that limits CCh-stimulated chloride secretion across intestinal epithelia.  (+info)

Ovulation induction and antifertility effects of an LH-RH analogue (AY 25,205) in cyclic rats. (4/96)

Pro-oestrous rats, treated with fluphenazine dihydrochloride to block ovulation, were used to compare the ovulation-inducing activity of synthetic LH-RH with one of its analogues, [D-Ala-6, des-Gly-NH2-10]-LH-RH ethylamide (AY-25,205). The lowest dose of LH-RH which produced a significant response was 125 ng compared with 2.9 ng AY-25,205. Statistical analysis of the data showed that AY-25,205 was approximately thirty-six times more potent than LH-RH. Treatment with AY-25,205 also induced partial ovulation in metoestrous rats (80 or 160 ng/rat) and apparently normal ovulation in dioestrous rats (10 to 160 ng/rat). The compound (160 ng) failed to induce further ovulation in oestrous rats which ovulated during the previous night. Advancement of premature ovulation in dioestrous rats with AY-25,205 prevented mating behaviour and pregnancy during the treatment cycle. The antifertility effect of the compound disappeared during the following cycle.  (+info)

Antimutagenic activity of fluphenazine in short-term tests. (5/96)

Fluphenazine, an antipsychotic drug that belongs to the phenothiazine family, reduced the genotoxicity of direct- and indirect-acting mutagens in the Ames test, both in the presence and in the absence of promutagen-activating S9 fraction. In short-term tests on human lymphocytes, the inhibitory effect of fluphenazine on the genotoxicity of standard mutagens was strongest in the cytokinesis-blocked micronucleus assay and in the thioguanine resistance test, and weakest in the sister chromatid exchange test. Fluphenazine also considerably reduced the level of free radicals estimated in in vitro samples of human granulocytes. The results suggest that, in the range of the tested concentrations, fluphenazine could be considered for use to prevent the genotoxicity of daunorubicin, methyl methanesulfonate, benzo[a]pyrene, and mitomycin C. Reduction in the level of free radicals appears to be an important mechanism of the antimutagenic action of fluphenazine.  (+info)

Effect of fluphenazine on tissue noradrenaline concentrations and its interaction with pargyline. (6/96)

Fluphenazine caused a small decrease in the noradrenaline (NA) concentrations of the rat brain, possibly by impairing granular amine storage. The drug diminished the rise in brain and heart NA concentrations induced by pargyline, suggesting that it might posses inhibitory properties on neuronal uptake mechanisms and/or NA synthesis. Fluphenazine abolished conditioned avoidance responses in rats, an effect which was maintained after the concomitant administration of pargyline, when NA concentrations remained high. This suggests that the fluphenazine-induced sedation is not mediated via its effect on brain NA content, but is possibly due to the effect of the drug on NA turnover rates in the brain.  (+info)

Neuroleptic effects on autonomic activity in schizophrenia: between-group and within-subject paradigms and comparisons with controls. (7/96)

Effects of fluphenazine on electrodermal activity (EDA) and heart rate (HR) were studied in patients with schizophrenia and normal control subjects during rest periods, presentation of innocuous tones, and a reaction time (RT) task. Two types of analyses were used: (1) between-group analyses-patients taking placebo were compared with patients taking fluphenazine and with control subjects using only data from the first test session; and (2) within-subject analyses-the same patients were tested when taking fluphenazine and when taking placebo. Results showed higher resting EDA and HR and smaller increments to task performance in placebo patients than in control subjects. Fluphenazine attenuated EDA levels but not the tonic response. Fluphenazine attenuated the HR response but did not affect HR level. Placebo patients were electrodermally hyporesponsive to the RT stimuli but not to simple tones. Fluphenazine markedly attenuated responsivity to simple tones but it attenuated responsivity less for RT stimuli. Testing medicated patients may thus produce misleading results with respect to many, but not all, purported autonomic markers of diagnosis in schizophrenia studies.  (+info)

Prospective study of psychobiology in first-episode schizophrenia at Hillside Hospital. (8/96)

Heterogeneity has been a consistent problem in the research and treatment of schizophrenia. Despite marked variation in the onset, phenomenology, treatment response and outcome of schizophrenic patients, our ability to identify subtypes is remarkably limited. A major problem in schizophrenia research has been the use of cross-sectional study designs and heterogeneous patient samples at different stages of the illness and who have been previously exposed to neuroleptics which have potentially confounding effects on the disease. This study intends to identify biologic correlates of the phenomenology and course of schizophrenia by using a prospective, longitudinal, repeated measures design assessing biologic and clinical parameters including measures of psychopathology, side effects, and social adjustment to examine clinical variables of treatment response, illness course, and outcome; measures of central nervous system dopamine activity and brain morphology in patients, from the onset of their illness. Patients were ascertained at hospital admission and assessed with a battery of clinical, neuropsychologic, and biologic measures before undergoing standardized treatment for the acute and maintenance phases of the illness. Upon completion, approximately 120 first-episode patients will have entered the study and will have been followed prospectively for up to 5 years and assessed at specific time intervals. Preliminary results reveal significant abnormalities in brain morphology, growth hormone secretion, eye movement function, and psychotogenic response to dopamine agonists in first-episode, treatment-naive patients which are associated with treatment response and outcome. This article describes the study's rationale, design, and methods, and a summary of the published results to date. These are discussed in terms of their significance for putative clinical subtypes and pathophysiological models of schizophrenia.  (+info)