MJA practice essentials. 8. Psychoses: a primary care perspective.
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Family Practice↗
Biomedical subjects
D L Copolov
Publications and source records attributed to D L Copolov.
Typical and atypical neuroleptic drugs decrease platelet 3H-dopamine uptake in the rat.
Reports of opposing changes in platelet 3H-dopamine uptake in neuroleptic-free versus neuroleptic-treated schizophrenic subjects have suggested an effect of neuroleptic treatment on this measure. We examined platelet 3H-dopamine uptake in rats treated with haloperidol or clozapine to determine if such treatment did affect platelet 3H-dopamine uptake. Neuroleptic drug treatment reduced platelet 3H-dopamine uptake in a dose- and time-dependent manner. After up to 4 weeks of treatment, these effects were reversed by the discontinuation of neuroleptic drug treatment. These data suggest that the effect of neuroleptic treatment in studies of platelet 3H-dopamine uptake could account for the variable findings in schizophrenia.
Animals↗
Ascorbic acid augments the adenylyl cyclase-cAMP system mediated POMC mRNA expression and beta-endorphin secretion from hypothalamic neurons in culture.
Besides acting as an important cofactor in the biosynthesis of catecholamine, ascorbic acid (AA) also modulates the activity of peptidylglycine-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 of immunoreactive beta-endorphin (ir-beta EP) and mRNA expression of proopiomelanocortin (POMC) following the activation of cAMP-dependent protein kinase A pathway 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 in the presence or absence of forskolin, 3-isobutyl-1-methylxanthine (IBMX), N6,2'-O-dibutyryladenosine 3'5'-(cyclic)monophosphate [(Bu)2cAMP]. Whereas the basal ir-beta EP release was 22.0 +/- 0.4 pg/well (mean +/- S.E.; n = 3), 10 microM of forskolin treatment increased ir-beta EP release approximately 4.2-fold. Co-incubation with AA enhanced forskolin induced ir-beta EP release and that this enhancing effect of AA was both time related and dose-dependent, with an ED50 of approximately 10 microM and an Emax of 100 microM. At the concentration of 10 microM, AA augmented ir-beta EP release approximately 6.1-fold that of cultures treated with forskolin alone. A similar potentiating effect of AA was also seen in cultures co-treated with IBMX or with (Bu)2cAMP. These enhancing effects of AA were similarly found in the abundance of total cAMP and of POMC mRNA of cultures which received identical treatments. However, it is important to point out that AA alone did not modulate ir-beta EP release or the abundance of POMC mRNA or total cAMP levels of the hypothalamic cultures when protein kinase A pathway was not activated. We thus conclude that AA augments cAMP-dependent protein kinase A pathway-induced production and release of beta EP from rat hypothalamic neurons in culture. Furthermore, this biological effect of AA is, at least in part, mediated through enhancing the responsiveness of the adenylyl cyclase-cAMP system.
1-Methyl-3-isobutylxanthine↗
Serotonin2 receptors and the serotonin transporter in the schizophrenic brain.
The binding of [3H]paroxetine and [3H]ketanserin to particulate membranes from frontal cortex of subjects who had or did not have schizophrenia was measured as was [3H]paroxetine binding to particulate membranes from the hippocampus and caudate nucleus. There was no change in either the affinity or density of [3H]ketanserin binding to membranes from the frontal cortex of subjects who had schizophrenia. Similarly, there was no difference in the density of [3H]paroxetine binding to membranes from subjects who had or did not have schizophrenia. The affinity of [3H]paroxetine binding in the frontal cortex and putamen did not differ in subjects who had schizophrenia. By contrast, there was a significant decrease in the affinity of [3H]paroxetine binding to the hippocampal membrane from subjects who had schizophrenia (0.40 +/- 0.06 nM vs 0.26 +/- 0.02 nM; p < 0.05). Furthermore, this difference was more apparent in the subjects who had schizophrenia and committed suicide (0.49 +/- 0.09 nM) than it was in those who had schizophrenia but did not commit suicide (0.32 +/- 0.09 nM). As [3H]ketanserin binds to the serotonin2 receptor our data suggest that this receptor is not changed in the Brodmann's area 9 of the frontal cortex. By contrast, [3H]paroxetine binds to the serotonin transporter and therefore our data suggest that the serotonin transporter is altered in the hippocampus of subjects with schizophrenia.
Adolescent↗
Platelet [3H]dopamine uptake is differentially affected by neuroleptic drug treatment in schizophrenia and schizophreniform disorder.
1. The uptake of [3H] dopamine was measured using platelet-rich plasma (PRP) from neuroleptic-free subjects and again, in some cases, after the subject had been treated with neuroleptic drugs. 2. There were no differences in [3H]dopamine uptake by PRP in subjects who were or were not mentally ill. 3. After treatment with neuroleptic drugs the Km for platelet [3H] dopamine uptake had increased in 76% of subjects with schizophrenia and 87% of subjects with schizophreniform disorder. Similarly, the Vmax for platelet [3H]dopamine uptake had increased in 81% of the subjects with schizophrenia and 86% of the subjects with schizophreniform disorder. 4. By contrast, the Km for platelet [3H]dopamine uptake had decreased in 94% of subjects who had a psychoses associated with an illness other than schizophrenia or schizophreniform-disorder whilst the Vmax for platelet [3H]dopamine uptake also decreased by 94% in these subjects. 5. In subjects with psychoses, platelet [(3)H] dopamine uptake is differentially altered during neuroleptic drug treatment depending on diagnosis.
Adult↗
Treatment with haloperidol or clozapine causes changes in dopamine receptors but not adenylate cyclase or protein kinase C in the rat forebrain.
The effect of treating rats with daily injections of haloperidol (1 mg/kg/day) or clozapine (20 mg/kg/day) for four weeks on second messengers and dopamine receptors was studied. The binding of [3H]forskolin to adenylate cyclase (AC), [3H]phorbol 12,13-dibutyrate (PDBu) to protein kinase C (PKC), [3H]SCH23390 binding to the dopamine D1 (DA-D1) receptor and [3H]spiperone binding to the dopamine D2 (DA-D2) receptor were measured using quantitative autoradiography. The density of AC was greatest in the caudate-putamen, nucleus accumbens and olfactory tubercle, a distribution resembling that of DA-D1 receptor. The distribution of PKC was relatively homogeneous in the forebrain. Neither haloperidol nor clozapine administration significantly altered the levels of AC or PKC in the caudate-putamen. By contrast treatment with haloperidol, but not clozapine, significantly increased the density of DA-D2 receptors in the caudate-putamen without affecting the density of DA-D1 receptors. By contrast, both haloperidol and clozapine increased the density of DA-D1 receptors in the olfactory tubercle.
Adenylyl Cyclases↗
Patients' strategies for coping with auditory hallucinations.
Many patients with psychotic disorders experience persistent auditory hallucinations despite rigorous pharmacological treatment. The experience of auditory hallucinations can heighten anxiety and depression. The high risk of suicide among patients experiencing auditory hallucinations is well recognized. Research in this area has been restricted to small samples or has collected information only on the use of such strategies without investigating their efficacy. The Mental Health Research Institute Unusual Perceptions Schedule incorporates a module focusing on coping strategies. This schedule was administered to 100 subjects, with the aim of investigating the relationship between strategy use and effectiveness, as well as the characteristics of subjects and their disorders. Eighty-one percent of the subjects were worried or upset by their hallucinations. The majority (66%) of the subjects reported they had ways of managing the voices, and 69% of them described at least some success using one or more strategies. There was a striking lack of correspondence between the number of subjects using a method and its related efficacy. No relationship was found between length of illness and number of strategies used. Multidimensional scaling of use and efficacy data revealed three groups of strategies. These groups do not correspond to previous classifications made on the basis of features of the strategies themselves. The pattern of results also suggests that training methods might be used to increase the options for patients troubled by auditory hallucinations.
Adaptation, Psychological↗
The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia.
Changes in cholinergic neurons have been implicated in the pathology of schizophrenia. Clozapine, an atypical anti-psychotic drug, has been shown to bind with high affinity to the muscarinic1 (M1) receptor suggesting this receptor could be involved in the therapeutic efficacy of the drug. Because of this we measured the density of M1 receptors in the caudate-putamen, obtained at autopsy, from 19 schizophrenic subjects and 19 non-schizophrenic subjects. The density of M1 receptors was decreased in the caudate-putamen from the schizophrenic subjects (181 +/- 20 vs 287 +/- 10 fmol mg-1 TE; mean +/- s.e.m.; P < 0.001). Furthermore, preliminary studies would not suggest that the change in the density of M1 receptors in the tissue from the schizophrenic subjects had resulted from drug treatment prior to death. These data raise the possibility that changes in muscarinic receptors may be involved in the pathology of schizophrenia.
Adult↗
Glutamate enhances the adenylyl cyclase-cAMP system-induced beta-endorphin secretion and POMC mRNA expression in rat hypothalamic neurons in culture: NMDA receptor-mediated modulation.
L-Glutamate, a major excitatory amino acid of the central nervous system, plays important roles as neurotransmitter and neuromodulator in the brain. Increasing evidence suggests that glutamate may also involve in the regulation of the neuroendocrine system at the hypothalamus. Employing long term monolayer hypothalamic cell cultures prepared from neonatal rats, we reported here that whereas glutamate significantly enhanced forskolin-, or N6,2'-O-dibutyryladenosine-3'5'-cyclic monophosphate [(Bu)2cAMP]-stimulated immunoreactive (ir)-beta EP release from cultures treated daily for 4 consecutive days, the excitatory amino acid alone produced little effect. This potentiation of glutamate was time-related and dose-dependent with an Emax value of the amino acid being approximately 50 microM; at this concentration glutamate augmented ir-beta EP secretion about 1.8 times (P < 0.05) that induced by 2 microM forskolin alone. Similar effects were also observed for POMC mRNA levels in cultures subjected to 6 h of the above treatment regime. This potentiating effect of glutamate appears to be mediated specifically through NMDA receptor as it can be mimicked by NMDA but not by kainic acid or quisqualic acid, and blocked by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (APV), but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist. Interestingly, glutamate was found not to enhance high doses of forskolin (10 microM) or (Bu)2cAMP (100 microM) stimulated beta EP release and POMC mRNA levels in hypothalamic cell cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗
The development and reliability of the Mental Health Research Institute Unusual Perceptions Schedule (MUPS): an instrument to record auditory hallucinatory experience.
The Mental Health Research Institute Unusual Perceptions Schedule (MUPS) is a comprehensive instrument developed to record subjects' experiences of auditory hallucinations as completely as possible. The Schedule comprises a semi-structured interview and documents the physical characteristics of auditory hallucinations such as their onset and course, number, volume, tone, location, as well as other phenomena associated with them such as delusions. In addition, other aspects of hallucinations, such as coping strategies, contributing factors and subjects' personal views and reactions are also explored. In a sample of 100 subjects drawn primarily from the in-patient wards at Royal Park Hospital the MUPS was found to be an acceptable instrument to subjects in the field. Interrater reliability assessed in a subsample of 30 subjects was found to be high at the level of the individual items. Whether used in whole or part, the MUPS provides a reliable and acceptable method of assessing patients' experience of auditory hallucinations.
Adaptation, Psychological↗
Basal and haloperidol-stimulated prolactin and symptoms of nonaffective and affective psychoses in neuroleptic-free men.
The prolactin (PRL) response to 0.5 mg of intravenous haloperidol (HPL) IV may be a measure of tuberoinfundibular dopaminergic activity. Our earlier reports, using multidiagnostic strategies in schizophrenia, suggested that psychoses characterized by the absence of affective syndromes (Keks et al 1990) and the presence of thought disorder and passivity delusions (Keks et al 1992) are linked to blunted PRL responses. In this paper we evaluated the relationships between basal and HPL-stimulated PRL concentrations, and a number of potentially relevant symptom measures. Basal PRL was lower in patients without a depressive syndrome and suicidal ideation. Stimulated PRL was lower in patients without neurovegetative symptoms (versus patients with neurovegetative symptoms and controls), with depression (versus patients with no depression and controls) and those with disorder of associations (versus patients without association disturbance and controls). These findings can be interpreted as indicating a link between endocrine measures of dopaminergic function and a subtype of schizophrenic psychosis characterized by the presence of thinking disturbance in the absence of depression.
Adult↗
[3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from subjects with schizophrenia.
[3H]Paroxetine binding to particulate membrane from tissue, obtained at autopsy, from the hippocampus, frontal cortex, and caudate nucleus from subjects who had or had not had schizophrenia was measured. The density of [3H]paroxetine binding to membranes from subjects who had or had not had schizophrenia did not differ. Similarly, the affinity of [3H]paroxetine binding in the frontal cortex and caudate nucleus was not different. By contrast, the affinity of [3H]paroxetine binding to hippocampal membrane from subjects who had schizophrenia was significantly lower than the affinity of binding for the nonschizophrenic subjects (0.40 +/- 0.06 vs. 0.26 +/- 0.02; p < 0.05). As [3H]paroxetine binds to the serotonin transporter, these data suggest that the serotonin transporter is altered in the hippocampus in subjects with schizophrenia.
Adult↗
Glucocorticoids inhibit D1B, but not D2, receptor-mediated effects on hypothalamic atrial natriuretic factor neurons.
Recent evidence suggests that ANF neurons of the hypothalamus are dopamine sensitive, and the catecholamine may exert a direct stimulatory or inhibitory effect on the neurons mediated through D1 or D2 receptors, respectively, in a manner related to the differential dopamine binding sensitivity of the two receptor subtypes. Employing well characterized ANF RIA and colorimetric Northern blot analysis with synthetic oligonucleotide probes complementary to pro-ANF messenger RNA (mRNA), we report here the effect of dexamethasone (DM), a potent synthetic glucocorticoid, on DA-stimulated ANF neurons in long term primary cultures of neonatal rat hypothalamic cells. Although DM alone did not affect basal secretion of immunoreactive ANF, it approximately halved immunoreactive ANF secretion induced by D1 agonist, SKF38393 (P < 0.01). The effect of DM was both time dependent and dose related, with an EC50 of 0.1 nM; it was blocked by 100 nM RU38486 (P < 0.05), a glucocorticoid receptor antagonist, but not by 100 nM RU28318, a mineralocorticoid receptor antagonist. In addition, the effect of DM was mimicked by corticosterone (EC50, 10 nM), but not deoxycorticosterone. The increased expression of pro-ANF mRNA signal induced by the D1 agonist in culture was suppressed by DM in a similar manner. In contrast, DM did not modulate ANF production and secretion induced by D2 agonist, quinpirole. Furthermore, reverse transcription-polymerase chain reaction demonstrated that D1B, but not D2, receptor mRNA expression was selectively suppressed by glucocorticoids. Thus, we conclude that in monolayer cultures of rat hypothalamic neurons, glucocorticoids differentially modulate dopamine receptor-induced responsiveness of ANF neurons by down-regulating D1B, but not D2, receptor-mediated changes. Hence, in severe stress, high levels of circulating glucocorticoids may negate the D1B-induced stimulatory response but allow dopamine to suppress the function of hypothalamic ANF neurons through D2 receptor activation.
Animals↗
The development of a method to measure [3H] dopamine uptake by washed platelets provides no evidence for circulating inhibitors of platelet dopamine uptake in schizophrenia.
Altered [3H] dopamine uptake by platelet-rich plasma (PRP) has been reported in some subjects with schizophrenia (Rotman et al 1980; Dean et al 1990). As platelet dopamine uptake was measured using PRP, it was not possible to determine if the changes in schizophrenia were intrinsic to the platelet or due to plasma factors. Furthermore, the constraints of plasma as a medium for platelet suspension has hindered the study of the physiological requirements of platelet dopamine uptake. A method is now reported that allows platelets to be suspended in a controlled medium while preserving the dopamine uptake mechanism of the platelet. Dopamine uptake by platelets in a controlled medium was dependent on temperature, energy, sodium, and chloride. Furthermore, plasma from subjects with schizophrenia and schizophreniform disorder did not significantly alter [3H] dopamine uptake by platelets compared to the effect of plasma from control subjects. Hence, these data provide no evidence for a circulating inhibitor of platelet [3H] dopamine uptake in plasma from subjects with schizophrenia.
Blood Platelets↗
Glucocorticoids potentiate the adenylyl cyclase-cAMP system mediated immunoreactive beta-endorphin production and secretion from hypothalamic neurons in culture.
Beta-endorphin(beta EP)1-31, a potent opioid peptide of proopiomelanocortin (POMC) derivatives, is produced and released from neurons at arcuate nuclei of the rat hypothalamus. Although dexamethasone (DM) suppresses the production and secretion of POMC related peptides from rat pituitary corticotrophs, the effect of glucocorticoids on the function of hypothalamic beta EP neurons remains unclear. Employing long term monolayer cultures of neonatal rat hypothalamic cells, we report here that 4 day treatment with 10 microM of forskolin increased ir-beta EP levels in cell content and culture media by approximately 1.7 (P < 0.05) and 4.1 times (P < 0.01) above vehicle treated control cultures (mean +/- S.E.M., 47.3 +/- 2.6 pg/well and 40.4 +/- 3.0 pg/well; n = 3) respectively. Although 4 day treatment with DM alone had little effect on the release and the cell content of ir-beta EP, it significantly enhanced forskolin-induced elevation of ir-beta EP levels in cell content and in culture media. The effect of DM was dose-related and time-dependent, with an EC50 of about 1 nM; at this concentration DM enhanced ir-beta EP secretion about 2.1 times (P < 0.01) above that induced by 10 microM of forskolin alone. Furthermore, the potentiating effect of DM was specifically suppressed by 100 nM of RU38486 (P < 0.01), a glucocorticoid receptor antagonist, but not by an equivalent dose of RU28318, a mineralocorticoid receptor antagonist. In addition, Northern blot analysis showed that forskolin (10 microM) increased the abundance of POMC mRNA 1.4 fold above that of vehicle treated control cultures. Whereas by itself, DM (10 nM) had little effect on the level of POMC mRNA, it enhanced forskolin-stimulated increase of the abundance of POMC mRNA approximately 2.6 times. Moreover, DM also augmented 1.6 times (P < 0.05) forskolin-induced but not 3-isobutyl-1-methylxanthine (IBMX)-induced increase of cAMP production (5.5 +/- 0.4 pmol/well; mean +/- S.E.M., n = 3) in the cultures. Taken together, our findings suggest that in contrast to the inhibitory effect on pituitary corticotrophs, glucocorticoids enhance the production and secretion of beta EP from rat hypothalamic neurons by facilitating the stimulatory effect mediated, in part, through the adenylyl cyclase-cAMP system.
1-Methyl-3-isobutylxanthine↗
D2 receptors mediate dopamine suppression of irANF release and pro-ANF mRNA expression of rat hypothalamic neurons in culture.
Although N-terminal truncated forms of atrial natriuretic factor (ANF) are produced and released from rat hypothalamic neurons, the intrahypothalamic regulation of these processes remains unclear. Employing a well-characterized hypothalamic cell culture system, we report here that dopamine, mediating through D2 receptors, inhibits the synthesis and release of ANF. In long-term cultures of hypothalamic neurons, daily treatment for 4 days with quinpirole, a D2 agonist, significantly suppressed the basal irANF release in a time-related and a dose-dependent manner. The ED50 and Emax of the drugs were 9.1 x 10(-8) M and 10(-5) M, respectively. This effect of quinpirole was mimicked by 10(-7) M of dopamine, a physiological ligand for D2 receptor. Furthermore, the suppressing effects of both quinpirole and dopamine were abolished by sulpiride, a D2 antagonist. Whereas 10(-6) M of forskolin treatment consistently enhanced the release of irANF through activating the adenylyl cyclase-cAMP system, this stimulatory effect was suppressed by quinpirole in a dose-related manner. In addition, the application of pertussis toxin, a bacterial toxin which inactivated G1 protein activity, reversed the suppressing effect of quinpirole or dopamine on irANF release. These immunoassay findings were accompanied by corresponding changes in the abundance of pro-ANF mRNA in the cultures as determined by colorimetric Northern blot analysis. By combining the techniques of in situ hybridization and immunocytochemistry, the mRNA of D2 receptor was colocalized with irANF at a single cell level by double fluorescent staining.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Colocalization of atrial natriuretic factor and beta-endorphin in rat thymic macrophages.
Recent demonstration of immunoreactive (IR) atrial natriuretic factor (ANF) and beta-endorphin (beta-EP) in the thymus prompted a reexamination of the distribution and cellular localization of the two peptides within that tissue. Double labeling immunohistochemistry was carried out on gelatin-embedded cryostat thymic sections of adult male Sprague-Dawley rats. Cells stained positive with antiserum (S118), raised against rANF(1-28), were colocalized in > 95% of cases with immunofluorescent staining of IR-beta-EP(1-31). The cells were found sparsely distributed along the corticomedullary junction and in subcapsular regions. In 1- or 5-day monolayer cultures of adherent thymic cells, 15-20% of the cells stained positive for either IR-ANF or IR-beta-EP. Under these conditions, > 95% of IR-ANF or IR-beta-EP positive cells were also fluorescence stained for the rat macrophage marker ED-1. Thus, taken together with previous reports, our present findings suggest that, in the rat thymus, both ANF and beta-EP are produced by the same population of macrophages. To further investigate their presence in the thymus, the contents and molecular species of the two peptides were compared over the developmental period of the animal using well-characterized radioimmunoassays (RIA). Both peptides significantly increased their contents between day 2 and day 60. However, in terms of concentration, IR-ANF at day 2 was approximately 50% higher than day 16 and five times greater that at day 60; in comparison the concentration of IR-beta-EP remained relatively constant and the only significant difference from day 2 being a slight increase in the day 16 animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Latent trait modelling of symptoms of schizophrenia.
Latent trait models were fitted to data for 149 schizophrenic or schizophreniform inpatients rated on the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) using the Rasch Extended Logistic Model. It was found that a reduction in the numbers of rating categories, from six to three or four led to consistencies in response while deletion of several items led to consistent scales of symptoms that accorded with an item response characterization. Behaviours included in the final scales varied in the numbers of categories, and in the range of symptom level covered by a category. Relationships between scores representing symptoms were found to be modelled better by a factor structure that included a third overlapping 'cognitive' factor in addition to the now traditional positive and negative factors, than by the original positive and negative factors alone.
Adult↗