Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats. 917 95

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.
 ...
PMID:BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. 920 9

Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamatergic antagonists can cause psychotic symptoms in otherwise normal humans, and exacerbate these symptoms in schizophrenics. These findings have led to a model of dopamine-glutamate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotropic glutamate receptors would be differentially regulated by antipsychotic treatment. To begin to address this question, we examined the regulation of mRNA levels of the AMPA (gluR1-gluR4), low affinity kainate (gluR5-gluR7), and high affinity kainate (KA1-KA2) receptor subunits by clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) treatment for 2 weeks. Both clozapine and haloperidol caused region-specific alterations in the mRNA levels of these subunits, but there was no differential regulation in the cortex vs. the striatum. Haloperidol caused a decrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapine treatment caused an increase in gluR7 mRNA expression, and a decrease in gluR3 mRNA expression, in both cortex and striatum while causing an increase in KA2 mRNA levels, and a decrease in gluR4 mRNA levels, in the striatum only. These dissimilarities may represent an interesting mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our understanding of dopamine-glutamate interactions in schizophrenia.
 ...
PMID:Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in rat cortex and striatum. 922 32

Cortical and hippocampal EEGs in animal models of schizophrenia were compared to those obtained with psychotomimetics or antipsychotic agents by utilizing power spectral analysis. Models of positive schizophrenic symptoms were created with methamphetamine (MAP) and cocaine, and a model of both negative and positive symptoms was created with PCP. MAP caused a prolonged decrease in the cortical EEG power spectra, cocaine caused a marked decrease for a short time, and PCP produced no significant changes. In the hippocampal spectra, MAP induced a marked increase in the T2(6.0-7.9 Hz)/ T1(4.0-5.9 Hz) ratio, PCP caused a decrease of this ratio after an initial increase, and cocaine produced no significant change. (An increase in the T2/T1 ratio represents a shift of theta waves to higher frequencies.) Since apomorphine (a DA agonist) and MK-801 (an NMDA antagonist) caused the T2/T1 ratio to increase, positive schizophrenic symptoms caused by MAP may be related to the DA and NMDA systems. 3-PPP (a sigma agonist) caused biphasic changes similar to those induced by PCP. Haloperidol and chlorpromazine caused a decrease of the T2/T1 ratio. These results indicate that cortical and hippocampal EEG power spectra (especially the hippocampal T2/T1 ratio) can be used to characterize both qualitatively and quantitatively models of schizophrenia.
 ...
PMID:Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine. 922 40

A 13-year-old boy with psychotic, depressive, and obsessive-compulsive symptoms initially presented with auditory and visual hallucinations and a lifetime of excessive worries about contamination. Family history was significant for schizophrenia and compulsive behavior. When treated with clomipramine 100 mg daily (plasma level 85 ng/mL), obsessive-compulsive symptoms but not the hallucinations improved significantly, and racing thoughts and grandiosity developed later. Haloperidol 0.5 mg daily reduced the psychotic symptoms but was poorly tolerated, and then trifluoperazine 3 mg daily was ineffective, so clomipramine was discontinued (without worsening of OCD symptoms). Trifluoperazine in combination with lithium 1500 mg daily (0.9 meq/L), and then with the addition of carbamazepine 250 mg daily (3.7 micrograms/mL), was only partially helpful. Dose reductions in any medication led to increased psychotic symptoms within days. Trifluoperazine was then replaced by risperidone 3 mg twice daily. Within 2 weeks of starting risperidone, psychotic symptoms ceased but the patient experienced an incapacitating exacerbation of obsessive-compulsive symptoms, experiencing the most severe symptoms in his illness. Sertraline 50 mg reduced the OCD symptoms only briefly. After 5 months on risperidone, risperidone and sertraline were discontinued, and the obsessive-compulsive symptoms significantly decreased within 2 weeks. These clinical observations suggest that even when risperidone has a therapeutic antipsychotic effect, it may exacerbate obsessive-compulsive symptoms in predisposed adolescents.
 ...
PMID:Differential response of psychotic and obsessive symptoms to risperidone in an adolescent. 923 6

Based on anatomical and biochemical observations a role of glutamate in schizophrenia has been postulated. In the present work we have investigated the gene expression for two families of NMDA receptor subunits (NR-1 and NR-2) following acute and chronic treatment with typical (haloperidol) and atypical (clozapine) antipsychotic drug (APD) in rats. A single injection of the two drugs elicited a significant increase in the mRNA levels of NR-2B in the nucleus accumbens, whereas only haloperidol was able to elevate NR-2A and NR-2B in the hippocampus. Following a 21 day treatment, significant differences in the regulatory pattern of NMDA-R subunits were observed. Haloperidol increased their mRNA levels in striatum whereas clozapine, consistent with its relatively weaker influence on nigro-striatal dopamine function, did not change the expression of NR subunits in this region. Both APD's were able to decrease the expression of NR-2 subunits in the hypothalamus, but only clozapine was capable of reducing NR-2C in frontal cortex and accumbens. The regulation of NMDA-R subunits in specific brain regions may represent a novel and important mechanism through which APD's exert some of their effects on brain function.
 ...
PMID:Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs. 940 28

Haloperidol is widely considered a reference standard in antipsychotic therapy and is commonly used in comparative studies of the efficacy and safety of antipsychotic medication. Comparative clinical trials have shown that the novel antipsychotic agent risperidone tends to have greater efficacy (i.e., clinical response defined as a > or = 20% reduction in total scores on the Positive and Negative Syndrome Scale) than haloperidol in patients with chronic schizophrenia and poses less risk of extrapyramidal symptoms (EPS). We used DerSimonian and Laird's random-effects model to analyze pooled patient data from available randomized, double-masked, comparative trials of risperidone and haloperidol in patients with schizophrenia treated for at least 4 weeks at recommended doses. The purpose of the analysis was to determine whether there are significant overall differences in the rates of patient clinical response, prescription of anticholinergic agents, and treatment dropout. Six of the nine trials revealed in a literature search met all criteria for inclusion in the meta-analysis. The meta-analysis showed that in patients with chronic schizophrenia, risperidone therapy is associated with significantly higher response rates, significantly less prescribing of anticholinergic medication, and significantly lower treatment dropout rates than haloperidol. These results demonstrate the greater treatment efficacy associated with risperidone compared with haloperidol and suggest both a lower incidence of EPS and improved treatment compliance.
 ...
PMID:Risperidone versus haloperidol: I. Meta-analysis of efficacy and safety. 952 4

Haloperidol is the most commonly used antipsychotic drug in the therapy of acute schizophrenia. Clinicians have been using therapeutic drug monitoring in an attempt to improve clinical application of this drug. The scale of interest in this area is emphasised by the large number of studies (about 50) concerning the serum concentration-therapeutic effect relationship (SCTER) of haloperidol, including 35 studies on patients with acute schizophrenia. However, conflicting results concerning the existence and position of a therapeutic window have emerged. This article aims to provide a comprehensive review of the study design of studies in patients with acute schizophrenia before the study data are used for decision-making. For this purpose, a reproducible system for the evaluation of studies in this special area, a so-called total study score (TSS), was developed on an empirical basis. Thus, insufficient study design was found to be a reason for negative results. On the other hand, in spite of a great variability, the majority of studies with good design provided evidence for a significant SCTER: a bisigmoidal dependence of clinical effect on haloperidol serum concentration. The therapeutic effects of haloperidol increase at low concentrations, and the concentration has a maximum effect at about 10 micrograms/L and again decreasing at higher concentrations. The data of 552 patients also fit to this model in a single scatter plot (pseudo-r2 = 0.076, p < 0.001). The position of the therapeutic window was determined at about 5.6 to 16.9 micrograms/L. Patients treated with serum concentrations within this optimal range had a significantly better response compared with outside this range (p < 0.001, Student t-test). Therefore, a quantitative synthesis of all available data by means of effect-size analysis provides a mean effect-size (g) = 0.499 +/- 0.182 (standard deviation) for the comparison of haloperidol-treatment with serum concentrations within versus outside the therapeutic window. Thus, because of this moderate positive effect, serum concentration assay of haloperidol is recommended for patients with acute schizophrenia in a therapeutic drug monitoring programme. The modalities of haloperidol therapeutic drug monitoring in clinical practice are discussed, e.g. patient selection, method and time for serum concentration measurement, influence of premedication and comedication, interpretation of results and dose adjustment. Clinical investigations into this subject should focus on covariates which are responsible for the variability of the SCTER. Serum concentration assay is advised for investigations of nonresponse to exclude patients with pseudo-drug resistance.
 ...
PMID:The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia. 953 84

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.
 ...
PMID:Chronic treatment with haloperidol diminishes the phencyclidine-induced sensorimotor gating deficit in rats. 960 34

The prototypical neuroleptic haloperidol and the atypical antipsychotic clozapine induce distinctly different patterns of c-fos expression in the forebrain. While haloperidol appears to increase c-fos expression via its D2 dopamine receptor antagonist properties, the receptor mechanisms by which clozapine produces its unique pattern of c-fos expression are not known. The present experiments sought to address this question by determining the phenotypes of neurons in which clozapine increases Fos-like immunoreactivity (FLI). Fos immunostaining combined with in situ hybridization histochemistry using a cDNA oligonucleotide probe for D3 receptor mRNA indicated that the great majority (95%) of clozapine-induced FLI neurons in the major island of Calleja (ICjM) express D3 receptors. Similarly, in the nucleus accumbens (NAc) and lateral septal nucleus (LSN), the majority of clozapine-induced FLI neurons express D3 receptor mRNA (NAc 69%; LS 73%). In marked contrast, haloperidol-induced FLI neurons failed to express D3 receptors in any brain region. Studies with oligonucleotide probes for enkephalin (ENK) and dynorphin (DYN) indicated that clozapine increases c-fos expression in both ENK and DYN containing neurons in the NAc (ENK 40%, DYN 53%) and LSN (ENK 32%, DYN 59%). Haloperidol also increases c-fos expression in ENK and DYN containing neurons, albeit in a different pattern (striatum: ENK 93%, DYN 20%; nucleus accumbens: ENK 46%, DYN 36%; lateral septum: ENK 29%, DYN 18%). The present results demonstrate that haloperidol and clozapine target different populations of neurons even in regions such as the NAc and LSN, where they both increase c-fos expression. In addition, the fact that the majority of clozapine-sensitive neurons in NAc, LSN, and ICjM express D3 receptors suggests that activity at these receptors may contribute to the unique clinical profile of this antipsychotic agent. These data indicate that D3 receptors may represent novel targets in the pharmacotherapy of schizophrenia.
 ...
PMID:Phenotypic characterization of neuroleptic-sensitive neurons in the forebrain: contrasting targets of haloperidol and clozapine. 962 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>