Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D4 and 5-hydroxytryptamine (5-HT)2A receptor antagonist, was examined in rats. 2. Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED50 3.7 mg kg-1), haloperidol (ED50 0.1 mg kg-1) and chlorpromazine (ED50 0.9 mg kg-1), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg-1, did not exceed 50%. 3. Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg-1, i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED50 0.4 mg kg-1, i.p., and 0.3 mg kg-1, p.o., respectively), clozapine (ED50 0.3 mg kg-1, i.p. and 0.8 mg kg-1, p.o., respectively), haloperidol (ED50 0.02 mg kg-1, i.p. and 0.1 mg kg-1, p.o., respectively), chlorpromazine (ED50 0.3 mg kg-1, i.p. and 3.3 mg kg-1, p.o., respectively). In contrast, the MAP (3 mg kg-1, i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not affected by NRA0045 or clozapine, at the highest dose given (30 mg kg-1, i.p.). Haloperidol (ED50 0.3 mg kg-1, i.p.) and chlorpromazine (ED50 4.8 mg kg-1, i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4. Extracellular single-unit recording studies demonstrated that MAP (1 mg kg-1, i.v.) decreased the firing rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg-1, i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg-1 (i.v.). Clozapine completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg-1, i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg-1, i.v.). Haloperidol completely reversed the inhibitory effects of MAP on A10 (ED50 0.03 mg kg-1, i.v.) and on A9 dopamine neurones (0.02 mg kg-1, i.v.). NRA0045, like clozapine, was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5. Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg-1, s.c.) was reversed significantly by NRA0045 (3 mg kg-1, i.p.), clozapine (3 mg kg-1, i.p.) and haloperidol (0.3 mg kg-1, i.p.). 6. Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03-0.3 mg kg-1, i.p.) and clozapine (0.1-1 mg kg-1, i.p.) significantly and dose-dependently shortened the PCP(1.25 mg kg-1, i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (0.01-0.1 mg kg-1, i.p.) did not significantly alter swimming latency. 7. These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.
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PMID:The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats. 917 95

Clozapine is an atypical neuroleptic that is increasingly used for the treatment of schizophrenia. An automated method was developed for the routine quantification of clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum and urine by column switching and online high-performance liquid chromatography with ultraviolet detection. The method included adsorption of clozapine and its metabolites on a cyanopropyl-coated clean-up column (10 microns; 10 mm x 4.0 mm ID), washing interfering serum constituents to waste by deionized water, and, after column switching, separation on C18 ODS Hypersil reversed-phase material (5 microns; 250 mm x 4.6 mm ID). The compounds of interest were separated and eluted in fewer than 20 minutes, using a mobile phase consisting of 37.5 acetonitril:62.5 water, containing 0.4% (vol/vol) tetramethylethylenediamine and adjusted to pH 6.5 with concentrated acetic acid. Ultraviolet-detection was performed at 254 nm. The determinations exhibited linearity between detector signal and drug concentrations in a range from 5 ng/ml to 50 micrograms/ml. As little as 10 ng/ml of clozapine and 20 or 30 ng/ml of the metabolites was quantifiable. Interferences with other psychotropic drugs, serum, or urine constituents were negligible. The automated procedure enables the analysis of clozapine and metabolites in serum or urine in less than 1 hour.
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PMID:Automated determination of clozapine and major metabolites in serum and urine. 926 93

For the past 20 years the most enduring explanation for schizophrenia has been the dopamine hypothesis, which proposes that the dopaminergic system is overactive in this widespread disease. Classically, the D2 receptor formed the core of the dopamine hypothesis since there was considerable evidence for elevations of D2 receptor levels in the brains of schizophrenic patients, and because these receptors served as the primary target in mediating antipsychotic effects of most neuroleptics. However, the dopamine D4 receptor has recently received particular attention in this context. This is because the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, displays a 10-fold higher affinity for D4 compared to D2 or D3 receptors. Furthermore, the concentration in plasma water of clinical doses ofclozapine correlates well with its in vitro binding affinity for D4, but not D2 or D3 receptors, suggesting that D4 is a potential target in mediating clozapine's antipsychotic effects. As well, marked elevations in the level of a D4-like site (not identical to the D4 receptor) has been seen in the striatum of postmortem schizophrenic brains, but not in control brains. Finally, the most interesting feature of the D4 receptor is perhaps the array of polymorphisms associated with it, creating structural diversity in this receptor that supercedes all other known catecholamine receptors. The existence of these D4 polymorphisms raises the possibility that structural variations of this receptor may be associated with an increased susceptibility to schizophrenia, or observed variations in individual response to clozapine treatment. However, several studies aimed at investigating these hypotheses could not establish a direct role of D4 in schizophrenia. Furthermore, no association was evident between the polymorphic forms of D4 and susceptibility to schizophrenia, or variable clozapine response. Nevertheless, investigations surrounding this receptor has been far from futile. The observations which support the idea that D4 might serve as a target for clozapine have significantly modified and extended our understanding of mechanisms underlying atypical antipsychotic treatment of schizophrenia, as well as the dopamine hypothesis for schizophrenia. Further characterization of this receptor may prove to be crucial in designing highly effective antipsychotic drugs with minimal contraindications.
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PMID:Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action. 927 87

Prepulse inhibition is a model in which a weak subthreshold stimulus (prepulse), presented to an individual before a strong stimulus (pulse), inhibits a startle response to the latter. A deficit of prepulse inhibition induced by dopaminomimetics and antagonists of NMDA receptors has been suggested as an animal model of the sensorimotor deficit in schizophrenia. The aim of the present study was to examine the effect of chronic treatment with the classic neuroleptic haloperidol on the disruption of prepulse inhibition induced by the uncompetitive antagonist of NMDA receptors phencyclidine (PCP, 5 mg/kg sc). Haloperidol in a dose of 1 mg/kg/day was given to rats in drinking water for 3 months. The PCP-induced reduction in prepulse inhibition was not reversed by short-term (4-day) haloperidol administration. In contrast, long-term treatment with haloperidol (6 weeks or 3 months) diminished the PCP-induced effect. The present study suggests that the improvement in sensorimotor gating in the PCP model in rats by prolonged treatment with haloperidol may reflect its antipsychotic action.
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PMID:Chronic treatment with haloperidol diminishes the phencyclidine-induced sensorimotor gating deficit in rats. 960 34

Schizophrenia affects prefrontal and temporal-limbic networks. These regions were examined by contrasting regional cerebral blood flow (rCBF) during executive (Wisconsin Card Sorting Test [WCST]), and declarative memory tasks (Paired Associate Recognition Test [PART]). The tasks, and a resting baseline, were administered to 15 patients with schizophrenia and 15 healthy controls during 10 min positron emission tomography 15O-water measures of rCBF. Patients were worse on both tasks. Controls activated inferior frontal, occipitotemporal, and temporal pole regions for both tasks. Similar results were obtained for controls matched to level of patient performance. Patients showed no activation of hypothesized regions during the WCST and activated the dorsolateral prefrontal cortex during the PART. On the PART, occipitotemporal activation correlated with better performance for controls only. Better WCST performance correlated with CBF increase in prefrontal regions for controls and in the parahippocampal gyrus for patients. Results suggest that schizophrenia may involve a breakdown in the integration of a frontotemporal network that is responsive to executive and declarative memory demands in healthy individuals.
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PMID:Frontotemporal cerebral blood flow change during executive and declarative memory tasks in schizophrenia: a positron emission tomography study. 967 96

The symptoms of schizophrenia are treated through the blockade of mesolimbic and mesocortical dopamine activity. However, if dopamine activity in the nigrostriatal region is also blocked, extrapyramidal syndromes (EPS) are induced, and EPS are a major cause of noncompliance. It is therefore important for antipsychotic drugs with selective pharmacological profiles to be developed. Animal models for limbic selectivity and dose-response separation between behavioural and pharmacological parameters, which are analogous to EPS and antipsychotic effects, can now be used to differentiate between novel antipsychotics with few or no EPS and classical antipsychotics. Schizophrenic patients also often experience cognitive dysfunction, and it is important that antipsychotic drugs are developed that do not exacerbate this. Again, animal models can be used to give an indication of whether a compound has any effect on cognition. Both behavioural and electrophysiological rat models indicate that novel antipsychotic drugs, such as sertindole, but not classical antipsychotic drugs, such as haloperidol, demonstrate marked limbic selectivity. Nonhuman primate models of EPS show that the novel antipsychotics have a much greater separation between dose-response curves for antipsychotic effect and the development of EPS. The Morris water maze confirmed that sertindole does not adversely affect spatial learning or memory in rats. This paper reports on the differentiation between classical and novel antipsychotics using animal models.
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PMID:Pharmacological differentiation of classical and novel antipsychotics. 969 Sep 64

The effect of chronic treatment with the tricyclic antidepressant drug, imipramine (10 mg/kg per day), the selective serotonin (5-HT) reuptake inhibitor, fluoxetine hydrochloride (10 mg/kg per day), and vehicle, in drinking water for 24-28 days followed by 3-5 days withdrawal, on extracellular dopamine levels was studied in rat nucleus accumbens by in vivo microdialysis. Basal extracellular dopamine levels in the nucleus accumbens were increased after chronic imipramine (12.7 +/- 1.5 fmol/20 microl per 30 min, P = 0.019), and moderately decreased after chronic fluoxetine (6.5 +/- 0.6, P = 0.047), as compared to the vehicle controls (9.1 +/- 0.7), determined by one-way analysis of variance (ANOVA). Repeated measure ANOVA indicated that the D-amphetamine sulfate (0.5 mg/kg, s.c.)-induced increase in extracellular dopamine levels in the nucleus accumbens was potentiated after chronic imipramine (P = 0.002), but unchanged after chronic fluoxetine (P = 0.83). The difference in the effect of amphetamine could be influenced by the significant differences in basal levels. However, these results were also confirmed by analysis of the net area under the curve (net-AUC) for a 180-min period (six samples): for chronic imipramine (337 +/- 45 fmol/180 min, P = 0.005) and chronic fluoxetine (249 +/- 38, P = 0.57), as compared to the vehicle controls (178 +/- 29), determined by one-way ANOVA. We suggest that the effect of treatment with these agents on mesolimbic dopamine is unlikely to be involved in their shared antidepressant action, but may be relevant to other aspects of the therapeutic profile of these two drugs, e.g. the switch into mania which is more common after treatment with imipramine than fluoxetine and exacerbation of positive symptoms in patients with schizophrenia or schizoaffective disorder.
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PMID:Differential effects of chronic imipramine and fluoxetine on basal and amphetamine-induced extracellular dopamine levels in rat nucleus accumbens. 969 3

We present the case report of a young woman who suffered from schizophrenia-like psychosis leading to polydipsia and consequent water intoxication. Because of progressive somnolence and epileptic seizures therapy on the intensive care unit became necessary. Findings of MRI and cerebrospinal fluid were consistent with the diagnosis of chronic inflammatory disease of the central nervous system. As other possible causes could be excluded, multiple sclerosis seemed to be most probable. Simultaneous incidence of schizophrenia and multiple sclerosis and the differential diagnosis of central pontine myelinolysis following hyponatremia are discussed.
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PMID:[Schizophreniform psychosis with polydipsia and electrolyte imbalance in multiple sclerosis]. 975 22

Hyponatremia/hypoosmolemia causes marked morbidity and prolongs hospital stays in a significant subset of schizophrenic patients. Case reports with methodological limitations suggest clozapine ameliorates this water imbalance. To more conclusively assess this possibility, we completed a 24-week open-label study in 8 male polydipsic hypoosmolemic schizophrenic inpatients. Subjects were treated initially for 6 weeks with a conventional neuroleptic, which was replaced by 300, 600, and 900 (if tolerated) mg/day of clozapine for sequential 6-week periods. On clozapine, mean plasma osmolality rose an average of 15.2 mosm/kg (95% CI: 5.5-25.0). Dosage of 300 mg/day of clozapine was sufficient to normalize plasma osmolality and was generally well tolerated. Clozapine appears to be the first effective pharmacotherapy for severe water imbalance in schizophrenia.
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PMID:Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome. 999 May 61

Human MRI studies have demonstrated that treatment with typical antipsychotics may increase the volume of the caudate nucleus while clozapine treatment is associated with either no change or a reversal of the previous volume increase. In this study four groups of seven rats were treated for 8 months with either the typical antipsychotic haloperidol, the atypical antipsychotic clozapine, the D2/D3 receptor antagonist raclopride, or vehicle (plain drinking water). Striatal sections were prepared using D1-like and D2-like receptor ligand autoradiography. Images (4-6 sections per rat, per ligand) were digitized and the area of the striatum was measured on each section. Rats treated with haloperidol did not have a larger mean striatum area than the control group on either D1- or D2-like ligand autoradiograms. Using the D2-like ligand autoradiograms, the clozapine treated animals had a smaller mean striatum area than the control group. Mean left striatum area was larger than mean right striatum area in each treatment group and in the control group. In contrast to the MRI findings reported in schizophrenia, the area of the striatum was not increased in rats treated with typical antipsychotic agents, but the clozapine-associated area reduction may parallel the clinical studies.
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PMID:Effects of chronic treatment with typical and atypical antipsychotic drugs on the rat striatum. 1032 19


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