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)

Arinami et al. (1994) reported an association between the Ser311/Cys311 variant of the DRD2 gene and schizophrenia in a Japanese population. We did not find statistically significant differences in the distribution of the allele frequencies between schizophrenics (103) and controls (97) in a case-control sample (chi 2 = 2.07; p = 0.150) or in 64 nuclear families with the haplotype relative risk (HRR) design (chi 2 = 0.13; p = 0.718). Our results seem to exclude a main involvement of this variant of the dopamine D2 receptor gene in the etiopathogenesis of schizophrenia.
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PMID:No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using a classical case control study and the haplotype relative risk. 918 10

The beta-adrenoceptor antagonist as well as serotonin 5-HT1 receptor antagonist, (-)alprenolol, was found to potentiate the disrupting effect of the noncompetitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (-)alprenolol. (-)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective beta-adrenoceptor antagonist property of (-)alprenolol, since combined pretreatment with the beta1- and beta2-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT2 selective receptor antagonist, MDL 100907, significantly reduced the (-)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT3 selective receptor antagonist, ondansetron, failed to do that. Finally, the (-)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D2 receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.
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PMID:(-)Alprenolol potentiates the disrupting effects of dizocilpine on sensorimotor function in the rat. 929 28

The effects of sulpiride, a dopamine D2 receptor antagonist, were studied on visual event-related potentials in a monkey performing in a visual oddball task in order to investigate receptor specific mechanisms in visuo-cognitive processes. Following the injection of 0.35 mg/kg sulpiride i.m., the amplitude and latency of the primary (P100) and cognitive (P300) components did not change significantly. When 1.05 mg/kg sulpiride was administered, the latency of the primary and cognitive components increased. The amplitude of the P100 component decreased, while that of the P300 component increased. These data suggest that D2 receptors play an important role in visuo-cognitive processes in both physiological and pathological conditions such as Parkinson's disease and schizophrenia.
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PMID:Dopamine D2 receptor blockade alters the primary and cognitive components of visual evoked potentials in the monkey, Macaca fascicularis. 931 Mar 9

Serotoninergic system is involved in the regulation of diverse biological and psychological functions and a variety of serotonin receptor subtypes represent a possible target for a new generation of medications. 5-HT receptors play an important role in both schizophrenia and depression. Modern strategies for treating schizophrenia profit from the existence of interaction between serotonin and dopamine systems. New drugs called serotonin-dopamine antagonists (SDAs) offer wider spectra of activity and lower extrapyramidal side effects liability. The principle of the SDAs is that the drug should be a potent serotonin 5-HT 2A antagonist, with slightly less potent dopamine D2 receptor-blocking properties. New pharmacological agents with great therapeutic potential and fewer side effects were recently developed also for the treatment of depression. Among these new antidepressives the serotonin selective reuptake inhibitors (SSRIs) currently play the most important role.
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PMID:[Serotonin and treatment of mental disorders. Present status and future perspectives]. 934 Jan 86

The influence of three selective monoamine receptor antagonists on spontaneous locomotion and on the hyperlocomotion induced by the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine) was investigated. The selective and potent 5-hydroxytryptamine (5-HT)2A receptor antagonist R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol (MDL100,907; M100907) displayed a clear-cut selectivity for reduction of MK-801-induced as compared to spontaneous locomotion, in that the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) blocked and even totally abolished by the highest dose, while the latter was only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. The selective dopamine D1 receptor antagonist (-)-[4aR, 10 aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl- benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a slight preference for the latter; spontaneous locomotion was dose-dependently diminished to approx. 10% of controls (at 8 mg/kg i.p.). The dopamine D2 receptor antagonist raclopride ([(-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.33, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomotion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several combinations of different doses of the 5-HT2A receptor antagonist and the dopamine D1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M100907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that the 5-HT2A receptor antagonist M100907 will have efficacy in treating this condition. The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine receptor antagonists, will be less prone to induce psychomotor side-effects. Ongoing clinical studies will hopefully give the answers in the near future.
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PMID:MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride. 936 62

Neuroleptic drugs have a high affinity for the dopamine D2 receptor (DRD2); therefore DRD2 is thought to be a candidate gene for schizophrenia. Arinami et al. have reported a positive association between schizophrenia and the Cys311 variant of the DRD2 gene. We determined the allele frequency of this polymorphism in 78 Okinawan schizophrenic patients and 112 control subjects. The patients and controls did not differ significantly in allele frequencies of Cys311.
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PMID:An association study between the Cys311 variant of dopamine D2 receptor gene and schizophrenia in the Okinawan population. 947 22

A possible dysregulation of dopaminergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses, in particular of paranoid-hallucinatory states, and of the manic episodes of bipolar affective disorder. In the present study we analysed allelic and genotypic variations of a recently described functional deletion/insertion variant (-141C Ins/Del) in the 5' flanking region of the human dopamine D2 receptor gene. We investigated a total of 620 unrelated individuals, comprising 260 schizophrenic patients, 70 patients with bipolar affective disorder, and 290 population controls. Analysis of the -141C Ins/Del variant revealed that the schizophrenic, bipolar affective and control groups did not differ significantly regarding genotype frequencies and allele frequencies. No evidence of an allelic association with either a family history of schizophrenic psychosis or a diagnosis of schizophrenia of the paranoid type (according to ICD 10) was found. Our findings indicate that the -141C Del variant in the 5' flanking region of the human dopamine D2 receptor gene is unlikely to play a substantial role in genetic predisposition to major psychiatric disorders in Caucasians.
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PMID:Insertion/deletion variant (-141C Ins/Del) in the 5' regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder. Short communication. 958 64

Quetiapine (Seroquel, ICI 204,636) is an atypical antipsychotic that is effective in the treatment of both positive and negative symptoms of schizophrenia, and has a low propensity to cause extrapyramidal symptoms. The compound has a relatively short plasma elimination half-life (approximately 7 h). However, since dopamine D2 receptor occupancies correlate poorly with plasma concentrations of antipsychotics, plasma elimination half-life may not predict either duration of clinical effect or dosing frequency. Accordingly, the efficacy and tolerability of three dosing regimens (450 mg/day given in two or three divided doses daily, and 50 mg/day given twice daily) were compared in a 6-week, double-blind, randomized, multicentre, parallel-group study. The study recruited hospitalized men and women aged 18-65 years meeting DSM-IIIR criteria for acute exacerbation of chronic or subchronic schizophrenia. Six hundred and eighteen patients were randomly assigned to treatment with quetiapine 150 mg tid (n = 209), 225 mg bd (n = 200), or a comparator dose of 25 mg bd (n = 209). At day 42, the last day of randomized treatment and the primary timepoint for efficacy, quetiapine 450 mg/day was more effective than 50 mg/day: 225 mg bd was consistently superior to 25 mg bd in all measures of efficacy (total BPRS, P = 0.006; CGI severity, CGI improvement and SANS, P < 0.03), and 150 mg tid was statistically significantly superior to 25 mg bd with respect to BPRS total score (P = 0.05). The 225 mg bd and 150 mg tid groups were not significantly different from each other with respect to any efficacy measure. Quetiapine was generally well tolerated. Extrapyramidal symptom (EPS) adverse events were generally rare, and occurred with similar frequencies in the two 450 mg/day groups. Quetiapine was not associated with sustained increases in plasma prolactin at any dose. These data support the atypical profile developed from preclinical studies and show that quetiapine is an effective, well tolerated antipsychotic that can be given twice daily.
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PMID:A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia. 963

Retinoid dysregulation may be an important factor in the etiology of schizophrenia. This hypothesis is supported by three independent lines of evidence that triangulate on retinoid involvement in schizophrenia: (i) congenital anomalies similar to those caused by retinoid dysfunction are found in schizophrenics and their relatives; (ii) those loci that have been suggestively linked to schizophrenia are also the loci of the genes of the retinoid cascade (convergent loci); and (iii) the transcriptional activation of the dopamine D2 receptor and numerous schizophrenia candidate genes is regulated by retinoic acid. These findings suggest a close causal relationship between retinoids and the underlying pathophysiological defects in schizophrenia. This leads to specific strategies for linkage analyses in schizophrenia. In view of the heterodimeric nature of the retinoid nuclear receptor transcription factors, e.g., retinoid X receptor beta at chromosome 6p21.3 and retinoic acid receptor beta at 3p24.3, two-locus linkage models incorporating genes of the retinoid cascade and their heterodimeric partners, e.g., peroxisome proliferator-activated receptor alpha at chromosome 22q12-q13 or nuclear-related receptor 1 at chromosome 2q22-q23, are proposed. New treatment modalities using retinoid analogs to alter the downstream expression of the dopamine receptors and other genes that are targets of retinoid regulation, and that are thought to be involved in schizophrenia, are suggested.
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PMID:Three independent lines of evidence suggest retinoids as causal to schizophrenia. 963 32

Since the discovery that the antipsychotic action of phenothiazines was mediated by dopamine D2 receptors, the dopamine system has been scrutinized for schizophrenia related abnormalities. The focus has been to create neuroleptics with improved antipsychotic profiles and reduced side effects. With the identification of multiple dopamine receptor subtypes, the hypotheses regarding the role of dopamine in schizophrenia and antipsychotic action of neuroleptics have been refined. Even after the molecular identification of newer dopamine D2-like receptor subtypes (D3 and D4), the dopamine D2 receptor is still considered the predominant site for antipsychotic action. However, there has been much debate concerning the modulatory role of other dopamine receptor sites in the mechanism of action of antipsychotic drugs. Specifically, the dopamine D4 receptor has received much attention in this regard, since the atypical antipsychotic agent, clozapine, preferentially blocks this receptor subtype as compared with dopamine D2 and D3 receptors. In this review we will highlight some of the observations and arguments regarding the involvement of the dopamine D2 and D4 receptor sites in the therapeutic efficacy of antipsychotic medication.
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PMID:Dopamine D2 and D4 receptor ligands: relation to antipsychotic action. 972 Oct 18


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