Initial Australian experience with the atypical antipsychotic clozapine.
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Adult↗
Biomedical subjects
D L Copolov
Publications and source records attributed to D L Copolov.
Growth hormone response to clonidine in neuroleptic-free patients with multidagnostically defined schizophrenia.
The role of alpha 2-adrenergic receptor sensitivity in schizophrenia was examined by measuring growth hormone (GH) response after the intravenous administration of clonidine (1.3 micrograms/kg) in 26 healthy control subjects and 26 neuroleptic-free, acutely psychotic patients with at least 1 out of 11 possible diagnoses of schizophrenia derived from a multidiagnostic psychopathological assessment. GH responses were significantly (0.01) lower than control values in schizophrenias defined by E. Bleuler, M. Bleuler, Schneider, Langfeldt, Taylor and Abrams, and Cloninger, but not in DSM-III, World Health Organization, Feighner, Kraepelian, and Research Diagnostic Criteria (RDC) schizophrenias. Eight patients with RDC schizoaffective disorder also had a blunted response. However, there were no correlations with any symptom measures. There were no differences between paranoid and nonparanoid patients, although there was a significant difference between nonparanoid patients and control subjects. These findings support the presence of noradrenergic dysfunction in some patients within the schizophrenia syndrome, possibly those whose illnesses have an affective component. The study also illustrates the need for simultaneous investigation of several different sets of diagnostic criteria for schizophrenia in neurobiological research.
Adolescent↗
Positive and negative symptoms in the psychoses. Re-analysis of published SAPS and SANS global ratings.
The validity of the simple dichotomy between positive and negative symptoms was examined by reanalysing the results of published studies using global ratings from Andreasen's SAPS and SANS. Global ratings from our own sample of 114 diagnostically heterogenous psychotic patients were also analysed. In none of the studies was a simple positive-negative dichotomy an adequate representation of symptom structure. The most commonly occurring structure consisted of three independent groups: Hallucinations/Delusions, Positive Thought Disorder and Negative Symptoms. These findings applied to both manic and schizophrenic groups of patients. An important implication of these results for future studies is that combining positive symptoms into a single scale is inappropriate because possibly differential relationships between Hallucinations/Delusions and Thought Disorder and a variety of external measures may be obscured by such a means of data reduction.
Affective Symptoms↗
The adenylyl cyclase-cyclic AMP system modulates morphological and functional development of hypothalamic beta-endorphin neurons in culture.
In rats, opioidergic beta-endorphin (beta EP1-31) is produced and released from neurons of arcuate nuclei in the hypothalamus. Although the neuropeptide has been implicated in sexual maturation and stress-induced reproductive dysfunction, the intra-hypothalamic regulation of beta EP neurons remains unclear. Employing long-term monolayer cultures of neonatal rat hypothalamic cells, we report here that 4 days of treatment with 10 microM forskolin increased approximately 3-fold (P < 0.01) the proportion of immunoreactive (ir)-beta EP positive neurons bearing neurites. In addition, treatment of forskolin also enhanced ir-beta EP release (634 +/- 59 pg/well; mean +/- SE, n = 4, P < 0.01) by 14-fold and ir-beta EP content (119 +/- 13 pg/well; P < 0.01) by 2-fold above that of vehicle-treated cultures; in both instances, the EC50 and the Emax of forskolin were approximately 10 microM and 100 microM, respectively. The forskolin-stimulated release of ir-beta EP was mimicked by cholera toxin and (Bu)2cAMP treatment in a dose-related manner, but not by pertussis toxin. Although by itself 3-isobutyl-1-methyl-xanthine (100 microM) only doubled ir-beta EP secretion, it markedly potentiated the stimulatory effect of forskolin. This forskolin-induced stimulation was reversible and in cultures re-exposed to the same drug within the first 24 h period, there was a marked increase in the stimulated release of ir-beta EP (P < 0.05); re-challenge of forskolin at later stages, however, induced a smaller but significant secretion of ir-beta EP (P < 0.01) compared to that of vehicle-treated control cultures. Sephadex G-50 gel chromatographic profile of the media prepared from forskolin-treated cultures revealed a major ir-beta EP peak of 3 K M(r). High-performance liquid chromatography analysis showed that ir-beta EP of the 3 K M(r) species was eluted with a retention time similar to that of synthetic rat beta EP1-31. We thus conclude that the adenylyl cyclase-cAMP system plays an important role in the modulation of beta EP1-31 production and release from hypothalamic beta EP neurons in culture. Furthermore, the functional responsiveness and the morphological development of these neurons are affected, at least in part, by the intrinsic activity of the adenylyl cyclase-cAMP system.
1-Methyl-3-isobutylxanthine↗
Ascorbic acid enhances forskolin-induced cyclic AMP production and pro-ANF mRNA expression of hypothalamic neurons in culture.
Besides acting as an important cofactor in the biosynthesis of catecholamine, ascorbic acid (AA) also modulates the activity of peptidyl-glycine alpha-amidating monooxygenase for the post-translational modification of neuropeptides such as alpha-MSH and TRH. We report here a novel action of AA in modulating the secretion and mRNA expression of atrial natriuretic factor (ANF) in rat hypothalamic neurons. Primary cultures of hypothalamic neurons from neonatal rats as previously described were employed in the present studies. Six days after plating, cultures were replenished with serum free media and incubated with vehicle or various doses of AA, alone or in the presence of forskolin. Treatment with AA alone significantly increased irANF secretion from the cultures in a time-related and a dose-dependent manner with an ED50 of approximately 3 microM and an Emax of 100 microM. At the concentration of 10 microM, AA augmented irANF release approximately 3 fold that of the controls (55 +/- 7 pg/well; mean +/- SE, n = 3; P < 0.01), but it failed to affect the abundance of pro-ANF mRNA in the cultures. However, 10 microM of AA markedly enhanced forskolin-induced irANF secretion and pro-ANF mRNA abundance of the cultured cells. This potentiating effect of AA on forskolin stimulation showed a good parallelism to the levels of cAMP produced in the hypothalamic cultures. We thus conclude that AA acts alone or in synergism with forskolin to stimulate the secretion and production of ANF in rat hypothalamic neurons; this latter effect may operate at the genomic level and is mediated, at least in part, through the protein kinase A dependent pathway.
Animals↗
In vitro evidence for atrial natriuretic factor-(5-28) production by macrophages of adult rat thymi.
Although recent evidence suggests the presence of the 15-kilodalton (K) mol wt (Mr) precursor of atrial natriuretic factor (ANF) and pro-ANF mRNA in the thymus of human and rat neonates, the cellular origin of the peptides in the tissues remains to be elucidated. We report here that in adult male rats, the 15K M(r) presumptive precursor for ANF and a smaller 3K M(r), N-terminal truncated congener of the peptide, ANF-(5-28), are localized in a small population of thymic macrophages. The production of ANF in the thymus was further confirmed by demonstrating the presence of a single band of pro-ANF mRNA signal of approximately 0.8 kilobases from the tissue extract, corresponding to that in the heart. To examine the distribution of pro-ANF mRNA at a cellular level, colorimetric in situ hybridization with digoxigenin-labeled 30-mer oligonucleotides complementary to the first 10-amino acid sequence of ANF-(1-28) was employed. Positive staining was found in thymic cells localized mainly in subcapsular areas, with diffuse staining of positive cells in both the cortex and medulla mainly concentrated around the cortico-medullary junction of the tissue. The identity of the ANF-positive cells was further investigated using a double staining technique to costain immunoreactive (ir) ANF and the macrophage markers ED1 and S22 or the T-cell marker OX-19 in both thymic sections and in monolayer cultures of thymic cells. In the latter, approximately 17% of the adherent cells stained positive for irANF after 48 h in culture. Of these cells, more than 95% also stained positive for the macrophage marker ED1, whereas approximately 36% of the ED1-positive cells were colocalized with irANF. In contrast, no irANF-positive cells were colocalised with the pan-T-cell marker OX-19. In tissue sections, irANF was found in cells distributed predominantly around the cortico-medullary junctions and subcapsular areas, with diffuse staining of the cells in the medullary and cortical regions. Sephadex G-50 gel chromatographic profiles of thymic extracts revealed a major peak of immunoreactivity consistent with 15K M(r) and a smaller peak that coeluted with rat ANF-(1-28) of 3K M(r). HPLC analysis of the 3K M(r) species showed a single peak of immunoreactivity, which eluted with a retention time identical to that of synthetic rat ANF-(5-28).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Coexpression of atrial natriuretic factor and beta-endorphin in a subpopulation of rat splenic macrophages: age-related differences.
Separate demonstration of immunoreactive (ir) atrial natriuretic factor (ANF) and ir-beta-endorphin (beta EP) in macrophages of the rat spleen prompted a reexamination of their distribution and cellular localization in addition to their developmental regulation. Double labeling immunohistochemistry was carried out on paraffin-embedded spleen sections of adult male Sprague-Dawley rats. Cells stained positive with antiserum (S118) raised against rat ANF-(99-126) were colocalized in more than 95% of cases with immunofluorescent staining of ir beta EP-(1-31) and distributed sparsely throughout the venous sinusoidal regions of the red pulp. In 1- or 5-day monolayer cultures of adherent splenocytes, 11-16% of the cells stained positive for either irANF or ir beta EP. Under these conditions, more than 95% of irANF- and ir beta EP-positive cells were also fluorescence stained for the histiocyte marker S22 or the rat macrophage marker ED-1. Colorimetric in situ hybridization similarly revealed signals for pro-ANF mRNA in more than 95% of ir beta EP-positive adherent cells. Thus, taken together with previous reports, our present findings suggest that in the rat spleen, both ANF and beta EP are produced by the same population of macrophages. However, the tissue levels and processing of the two peptides over the developmental period of the animal differed markedly in several ways. In splenic extracts of 2-day-old neonatal rats, Northern blot analysis and RIA revealed a greater abundance of pro-ANF mRNA signal and an irANF concentration about 6-fold greater than those in 30-day-old animals. In contrast, the ir beta EP concentration did not vary significantly over the same period, consistent with the level of POMC mRNA. Sephadex G-50 gel chromatography of splenic extracts from 2-day-old animals revealed predominantly higher mol wt forms of irANF and ir beta EP. From days 16-60, a significant proportion of irANF eluted in the same fractions as the mature circulating form, rat ANF-(99-126); the proportion of 3.5-kilodalton ir beta EP increased progressively to become the predominant species in adult tissues. Thus, it appears that although ANF and beta EP are coexpressed by the same population of splenic macrophages, they differ markedly during the developmental period with respect to their constitutive regulation.
Aging↗
Constructing a minimal diagnostic decision tree.
Classification trees and discriminant function analysis were employed in order to ascertain whether a small number of diagnostic decision rules could be extracted from a large inventory of items. Several models, involving up to 17 symptoms, that led to a broad psychiatric diagnosis were then tested on a small validation sample of 53 patients. All methods, with the exception of CART used without any pruning, generated identical trees involving four items. Almost 90% of the validation sample was able to be correctly classified by all methods although poor classification performance was noted in the case of one particular diagnosis, Schizoaffective Psychosis. In contrast, stepwise linear discriminant analysis originally selected 17 items, although three out of the first four items selected were identical to those chosen by the tree-building methods. Although more research is required, there are indications that the latter methods may be usefully employed in constructing parsimonious decision trees.
Algorithms↗
Identification of a dopamine-binding protein on the membrane of the human platelet.
The binding of [3H]dopamine to platelet membranes has been examined in an attempt to identify the putative dopamine-uptake mechanism of the platelet. [3H]Dopamine has been shown to bind to a 42,000 Da glycoprotein in platelet membrane with high affinity (Kd = 22.6 nM) and binding of [3H]dopamine was competed for by dopamine, molecules with catechol moieties, 5-hydroxytryptamine, GSH and ascorbic acid. Differences in pharmacological profile and molecular mass suggest that [3H]dopamine does not bind to a known receptor, a neuronal-type dopamine transporter or the platelet 5-hydroxytryptamine-uptake site. It is proposed that this novel binding site for dopamine, which has been purified 1000-fold from particulate platelet membrane, is likely to be a component of the dopamine-uptake mechanism of the human platelet.
Biological Transport↗
Multidiagnostic evaluation of prolactin response to haloperidol challenge in schizophrenia: maximal blunting in Kraepelinian patients.
We have previously reported that prolactin (PRL) responses to haloperidol 0.5 mg IV were blunted in subjects characterized by several diagnostic systems of schizophrenia compared to controls (Keks et al 1990). However, an attempt to find a diagnostic system most different from controls was unsuccessful due to inherent difficulties in the statistical analysis of multidiagnostic data. In this paper we present new methodologies. A test for differences in dependent correlations demonstrated that most of the variance in stimulated PRL was accounted for by Kraepelinian, and least by Schneiderian and M. Bleulerian, schizophrenias (p < 0.001). The main symptomatic difference between nonKraepelinian and Kraepelinian patients was the presence of association disturbance and feelings of passivity. Patients with both symptoms had a lower stimulated PRL than controls. Further findings and possible implications are discussed.
Adult↗
An assay to measure the simultaneous uptake of [3H]dopamine and [14C]serotonin by the human platelet reveals an imipramine-insensitive [3H]dopamine uptake mechanism.
To determine whether a specific dopamine uptake mechanism is present on the human platelet the simultaneous uptake of [3H]dopamine and [14C]serotonin by platelets was measured. Utilising a dual radiolabel uptake technique, platelets have been shown to take up serotonin more rapidly and to a greater extent than they take up dopamine. Furthermore, at high concentrations serotonin was able to reduce dopamine uptake by platelets by 60% whereas dopamine had no effect on serotonin uptake. Similarly, imipramine and reserpine reduced (97% and 74% respectively) serotonin uptake by platelets in a dose-dependent manner, but did not affect the uptake of dopamine. Our data show that platelets take up dopamine by a mechanism independent of the imipramine-sensitive serotonin uptake mechanism. Furthermore, the increased capacity of platelets to store serotonin is because serotonin, unlike dopamine, is transported into the dense granules of the platelet.
Biological Transport↗
Dopamine uptake by platelets from subjects with schizophrenia: a correlation with the delusional state of the patient.
The uptake of 3H-dopamine by platelets from patients with a number of psychiatric disorders has been compared with that by platelets from normal volunteers. Overall, 3H-dopamine uptake by platelet-rich plasma (PRP) from 25 schizophrenic subjects did not differ from 3H-dopamine uptake by PRP from 22 nonschizophrenic patients and 61 normal volunteers. In the schizophrenic group, however, there was an increased spread of results with seven values falling outside the range of results observed in the control group. Furthermore, of the patients rated, only for the schizophrenic patients was there an inverse correlation between 3H-dopamine uptake by platelets and the rating for delusions on the Scale for the Assessment of Positive Symptoms. Thus, 3H-dopamine uptake by platelet seems, in some way, to be linked to be delusional state of the patient. Further study of 3H-dopamine uptake by platelets is warranted in a larger and more diverse group of patients to determine the significance of altered dopamine uptake by platelets from some schizophrenic subjects and the correlation between platelet 3H-dopamine uptake and the delusional state of these subjects.
Adult↗
Positive and negative symptoms in the psychoses: multidimensional scaling of SAPS and SANS items.
Recently, the validity of the simple dichotomy between positive and negative symptoms in psychosis has been questioned. A newly admitted group of 114 DSM-III patients with psychotic disorder were assessed using Andreason's positive and negative symptoms scales. Multidimensional scaling, augmented by cluster analysis, was applied to the full item set of these scales and showed clearly that there are three major, independent groups of symptoms: Hallucinations/Delusions, Positive Thought Disorder and Negative Symptoms. Within the Hallucinations/Delusions and Negative Symptoms groups there was some additional structure which does not conform to the SAPS and SANS sub-scales. In particular there was considerable heterogeneity within the Hallucinations/Delusions group, and delusions of persecution may represent a fourth independent dimension of psychopathology which is under-represented in these scales.
Adult↗
Diagnostic concordance in functional psychosis revisited: a study of inter-relationships between alternative concepts of psychotic disorder.
More than a decade ago, a series of retrospective studies examined the concordance between proliferating definitions of severe psychiatric disorder. The European response has been a poly-diagnostic one, which has attempted to maintain interest in a broad range of psychiatric phenomena in the psychoses. In North America a more convergent approach has emerged, resulting in a series of operational definitions evolving from one another, and a correspondingly limited capacity to allow alternative perspectives to co-exist. The present study uses a prospective design as well as recent improvements in the clinical validity of psychopathology assessment to re-evaluate the relationships between competing concepts of psychotic illness in a broad sample (N = 176) of recent-onset psychotic patients. In the schizophrenic group, concordance was predictably highest among recent North American 'cousins', and lowest among various historical concepts. There was a moderately high concordance between selected schizoaffective and atypical psychosis definitions, indicating that this component is an important area for further studies of descriptive validity. These interrelationships may be used as a starting point to explore latent classes underlying the phenomena of functional psychosis.
Adult↗
Norepinephrine stimulates immunoreactive (ir) atrial natriuretic peptide (ANP) secretion and pro-ANP mRNA expression from rat hypothalamic neurons in culture: effects of alpha 2-adrenoceptors.
Although ANP or its smaller congeners are produced and secreted from rat hypothalami, the role or roles of neurotransmitter(s) in regulating their release and production from the neurons remains unclear. We report here that norepinephrine or epinephrine (NE/EPI) facilitates irANP secretion and pro-ANP mRNA expression in long term cultures of rat hypothalamic neurons through their effects on alpha 2-adrenoceptors. Hypothalami of 3 day-old Sprague-Dawley rats were removed and digested with collagenase. The dispersed cells were plated on poly-D-lysine coated culture dishes (10(6) cells/well) in Hepes buffered Dulbecco's Modified Eagle Medium supplemented with 8% fetal calf serum. Six days after plating, media were replenished with serum free media and the cultures incubated for 4 more days with vehicle or various doses of NE, EPI, alpha- or beta-adrenoceptor agonists in the presence of absence of antagonists. Culture media were then extracted with C18 Sep-pak and the levels of irANP determined by a well characterised RIA for ANP. NE or EPI treatment significantly increased irANP secretion from the cultures in a dose related manner with ED50 and Emax of approximately 0.2 microM and 1 microM respectively. The stimulation effect of NE was blocked by yohimbine (alpha 2-antagonist), but not prazosin (alpha 1-antagonist) or propranolol (beta-antagonist). Clonidine (alpha 2-agonist), but not phenylephrine (alpha 1-agonist) or isoprenaline (beta-agonist) mimicked the effects of NE or EPI. At the concentration of 0.1 microM, clonidine increased irANP release approximately 3 fold above that of control values (34.7 +/- 3.3; mean +/- SE, n = 4). These changes were accompanied by corresponding increments in the abundance of pro-ANP mRNA in the cultures as examined by a colorimetric Northern blot analysis. Our results indicate that NE or EPI, acting through its alpha 2-adrenoceptors, may modulate the function of ANP neurons in rat hypothalami by regulating the secretion and production of the neuropeptide at the genomic level.
Animals↗
In vitro evidence for modulation of morphological and functional development of hypothalamic immunoreactive atrial natriuretic peptide neurons by cyclic 3',5'-adenosine monophosphate.
In the hypothalamus of the rat, the precursor of atrial natriuretic peptide (ANP) is produced and processed into its smaller congeners of 3K mol wt species, which are secreted from neurons with cell bodies in the periventricular areas and the paraventricular nuclei of the tissue. Employing long term monolayer cultures of neonatal rat hypothalamic cells, we have identified a small population of cells that stained positive for immunoreactive (ir) ANP. Seventy-two +/- 7% (mean +/- SE; n = 4 per 1000 cells) of the irANP positive cells were colocalized with the staining of neuron-specific enolase; some of the cells possessed multiple neurites and showed irANP staining in the perikarya, in the varicosities along neuronal processes, and at the terminals of long neurites. Over the range of 10(-6)-10(-4) M, forskolin, 3-isobutyl-1-methylxanthine, or 8-bromo-cAMP significantly augmented the total number of irANP-positive cells and those possessing neurites in a dose-related and time-dependent manner. At 10(-4) M, 4 days of forskolin treatment increased the number of irANP-positive neurons 4-fold (P less than 0.01) while tripling that of the cells with long neurites (P less than 0.01). Furthermore, it approximately tripled the number of cells (P less than 0.01) showing positive signals for pro-ANP mRNA, as ascertained by colorimetric in situ hybridization using a 30-basepair antisense oligonucleotide probe labeled with digoxigenin. Consistent with the above observation, forskolin, 3-isobutyl-1-methylxanthine, or 8-bromo-cAMP treatment significantly augmented the total amount of irANP present in the cultures, with an ED50 of forskolin approximating 5 x 10(-5) M. Although treatment with 10(-7) M phorbol 12-myristate 13-acetate approximately doubled the production of irANP in the cultures (P less than 0.05), phorbol 12-myristate 13-acetate had little effect on modulating the number or neurite outgrowth of irANP neurons. Thus, our present findings suggest that protein kinase-A pathways are of greater importance than protein kinase-C pathways in regulating both the functional and morphological development of ANP-producing neurons during the ontogenesis of the rat hypothalamus.
1-Methyl-3-isobutylxanthine↗
Evidence for atrial natriuretic peptide-(5-28) production by rat placental cytotrophoblasts.
Atrial natriuretic peptide (ANP), a 28-amino acid peptide, is produced and secreted by cardiac atriocytes to modulate cardiovascular and renal functions. We report here the production of ANP-(5-28) and its 15K mol wt (M(r)) presumptive precursors by cytotrophoblasts of rat placentae. Placental tissues were collected from Sprague-Dawley fetal rats on days 12, 16, 18, and 20 of gestation and acid extracted for immunoreactive (ir) ANP assay. The contents of placental irANP increased over the course of fetal growth, with the highest amount (mean +/- SE, 1083 +/- 125 pg/tissue; n = 7) found near term. Sephadex G-50 gel chromatographic profiles of the placental extract revealed a major peak of irANP coeluted with the 3K M(r) of synthetic rat (r) ANP-(1-28) and a minor peak in the position consistent with that of 15K M(r). HPLC analysis of the 3K M(r) species showed a single peak of immunoreactivity, which eluted with a retention time similar to that of rANP-(5-28). In placental sections, irANP and pro-ANP mRNA were localized by immunoperoxidase staining and colorimetric in situ hybridization in a subpopulation of placental cytotrophoblasts, but not in syncytiotrophoblasts or chorionic cells. Northern blot analysis showed a single band of pro-ANP mRNA in rat placental tissues similar in size to that found in the heart (approximately 0.85 kilobases), with the highest level of pro-ANP mRNA signal detected in the placentae of 16-day gestation fetuses. Our findings suggest that ANP is expressed and produced by a small population of rat placental cytotrophoblasts and that the 15K M(r) precursor peptide is extensively processed into the N-terminal-truncated form of ANP-(5-28) in the tissue.
Animals↗
Plasticity of adrenoceptor responsiveness on irANP secretion and pro-ANP mRNA expression in hypothalamic neuron cultures: modulation by dexamethasone.
Atrial Natriuretic Peptide (ANP) or its smaller congeners are produced and secreted from the rat hypothalamus. Whereas immunoreactive (ir)ANP secretion and proANP mRNA expression in hypothalamic cell cultures of neonatal rats were augmented by norepinephrine acting through its alpha 2-adrenoceptors (AR), in the perifusion studies of adult hypothalamic fragments beta-AR was involved in the upregulation of irANP release. Here, we report that dexamethasone (DM) modulates irANP secretion and pro-ANP mRNA expression from hypothalamic neurons in culture by switching the adrenoceptor responsiveness of the cells from alpha 2- to that of beta-AR. In long term cultures of hypothalamic cells, treatment with clonidine (alpha 2-AR agonist) increased irANP secretion in a dose related manner. This effect of clonidine was abolished by DM, a glucocorticoid which by itself had little effect on the basal release of irANP. In contrast, isoprenaline, a beta-AR agonist which was ineffective when applied alone, enhanced irANP secretion from hypothalamic cultures in the presence of DM. Concurrent incubation of DM (5 nM) and isoprenaline (10 microM) augmented irANP release approximately 3 fold above that of cultures treated with DM alone (22.6 +/- 2.2; mean +/- SE, n = 4). However, phenylephrine, an alpha 1-AR agonist alone or in the presence of DM failed to stimulate irANP release. These immunoassay findings were accompanied by corresponding changes in the abundance of pro-ANP mRNA in the cultures as examined by colorimetric Northern blot analysis employing a 30 mer oligonucleotide probe corresponding to the first 10 amino acid sequence of rANP1-28. We conclude from the above observations that glucocorticoids modulate irANP secretion and pro-ANP mRNA expression in hypothalamic neurons by altering the responsiveness of the cells from alpha 2-AR to that of beta-AR.
Animals↗