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)

In the present study we describe the excitatory effects of the bioactive peptide neurotensin on the electrical activity of dopamine neurons (simultaneously recorded) in the substantia nigra pars compacta and the ventral tegmental area. The neurotensin fragment (8-13) induced comparable increases in firing rate of the substantia nigra and ventral tegmental area dopamine neurons (EC50 values 30 and 45 nM, respectively). The neurotensin receptor antagonist SR142948A antagonized the excitatory effects of neurotensin fragment (8-13) (pA2 values 8.4 and 8.2, respectively). Furthermore, it was found that a low concentration of neurotensin fragment (8-13) (1 nM) attenuated the inhibition of the firing rate by the selective dopamine D2 receptor agonist quinpirole in both neuron types (e.g., the effect of 0.01 microM quinpirole was reduced by approximately 60% in the presence of 1 nM neurotensin fragment [8-13]). Antagonism of this neurotensin fragment (8-13) effect by SR142948A confirms that neurotensin receptors can reduce the effect of dopamine D2 receptors at the single-cell level. These results are discussed in the light of possible roles for neurotensin in neurological disorders such as Parkinson's disease and schizophrenia.
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PMID:Neurotensin attenuates the quinpirole-induced inhibition of the firing rate of dopamine neurons in the rat substantia nigra pars compacta and the ventral tegmental area. 1065 21

Brain dopamine receptor agonists alleviate the signs of Parkinson's disease, while dopamine receptor antagonists alleviate hallucinations and delusions in psychosis. The dopamine type 2 receptor (or D2) is blocked by antipsychotic drugs, including even the "atypical" drugs such as clozapine or remoxipride, in direct relation to their clinical potencies. Compared to the long form of the D2 receptor (D2(Long)), the short form (D2(Short)) may be three times more sensitive to benzamide antipsychotic drugs. Hence, it is essential to identify additional variants of dopamine receptors for which more selective antipsychotic drugs can be found. Although no family linkage has been found between the D2 receptor and schizophrenia, there can be brain region abnormalities in the RNA transcript expression of dopamine receptors. Therefore, in order to identify variant dopamine D2 receptors, we searched for mutations in the RNA transcripts for the dopamine D2 receptor in the striatum of post-mortem brains from individuals who died with psychosis, including schizophrenia. A new splice variant of the D2 receptor, D2(Longer), with a unique TG splice site, was found in one control brain and in two psychotic brains.
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PMID:New dopamine receptor, D2(Longer), with unique TG splice site, in human brain. 1071 23

The Del allele of the -141C (Ins/Del) polymorphism located in the immediate 5'-flanking region of the human dopamine D2 receptor gene has been reported to be associated with reduced promoter activity in vitro. However, genetic association studies of the -141C (Ins/Del) polymorphism with schizophrenia and alcoholism have yielded conflicting results. In this report, we explored the effect of the Del allele on the D2 receptor binding characteristics in vivo in healthy volunteers using positron emission tomography and D2 receptor antagonist, [11C]raclopride. No difference in D2 receptor density was observed between the Del allele carriers compared to the individuals with the Ins/Ins genotype, indicating that the genetic variation at the -141C (Ins/Del) site does not affect D2 receptor expression level in vivo.
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PMID:The dopamine D2 receptor 5'-flanking variant, -141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo. 1078 Feb 70

The dopamine D2 receptor (D2) system has been implicated in several neurological and psychiatric disorders, such as schizophrenia and Parkinson's disease. There are two isoforms of the D2 receptor: the long form (D2L) and the short form (D2S). The two isoforms are generated by alternative splicing of the same gene and differ only by 29 amino acids in their protein structures. Little is known about the distinct functions of either D2 isoform, primarily because selective pharmacological agents are not available. We generated D2L receptor-deficient (D2L-/-) mice by making a subtle mutation in the D2 gene. D2L-/- mice (which still express functional D2S) displayed reduced levels of locomotion and rearing behavior. Interestingly, haloperidol produced significantly less catalepsy and inhibition of locomotor activity in D2L-/- mice. These findings suggest that D2L and D2S may contribute differentially to the regulation of certain motor functions and to the induction of the extrapyramidal side effects associated with the use of typical antipsychotic drugs (e.g., haloperidol). Quinpirole induced a similar initial suppression of locomotor activity in both D2L-/- and wild-type mice. In addition, the D2S receptor in the mutant mice functioned approximately equally well as did D2L as an impulse-modulating autoreceptor. This suggests that the functions of these two isoforms are not dependent on the formation of receptor heterodimers. Our findings may provide novel information for potentially developing improved antipsychotic drugs.
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PMID:Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. 1106 37

1. Previous reports showed that the A1 allele of Taq1 A dopamine D2 receptor polymorphism was associated with lowered density and diminished function of dopamine D2 receptor. In this study, association between Taq1 A dopamine D2 receptor polymorphism and psychopathology of schizophrenia was investigated. 2. The subjects were 61 acutely exacerbated schizophrenic patients who were all Japanese descent and had received no medication for at least one month before this study. Pretreatment psychotic symptoms were assessed by the Brief Psychiatric Rating Scale (BPRS). The Taq1 A genotypes, the A1 and A2 alleles, were determined by polymerase chain reaction method. 3. The patients were divided into three genotype groups; i.e., the patients with A1/A1 allele (n=6), those with A1/A2 allele (n=32) and those with A2/A2 allele (n=23). 4. There was no significant difference in total BPRS, subgrouped symptoms (positive, negative, anxiety-depression, excitement and cognitive symptoms) or any scores of BPRS items among the three Taq1 A genotype groups. 5. The present study suggests that Taq1 A dopamine D2 receptor polymorphism does not play an important role in psychopathological symptoms of schizophrenia.
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PMID:Association between Taq1 a dopamine D2 receptor polymorphism and psychopathology of schizophrenia in Japanese patients. 1113 Nov 75

"Atypical" antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a "pharmacological shotgun" strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.
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PMID:Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. 1116 Jul 92

The aim of this study was to compare the degree of striatal dopamine D2 receptor availability in patients treated with recommended (5-20 mg, mean dose 11.9 +/- 6.3 mg daily) and higher doses (25-40 mg, mean 32.1 +/- 5.6 mg daily) of the novel antipsychotic drug olanzapine by means of [123I] IBZM Single photon emission computed tomography (SPECT). The results were compared to those of a group of 10 untreated, healthy, age- and sex-matched controls. The degree of dopamine D2 receptor occupancy in the patient group was correlated with the presence of extrapyramidal symptoms (EPS). A total of 20 patients who met the DSM III R criteria for schizophrenia or schizoaffective disorder received a clinically effective antipsychotic monotherapy with olanzapine. The mean daily dose of olanzapine ranged from 0.05-0.6 mg/kg body weight. The dopamine D2 receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding expressed as the [STR-BKG]/BKG ratio ranged from 0.13-0.61 (healthy controls 0.95). The D2 receptor availability revealed an exponential dose-response relationship (r = - 0.85, p < 0.001). The frequency of EPS induced by olanzapine was considerably lower. Only one patient, treated with 40 mg olanzapine, suffered from severe EPS symptoms and had to be given biperiden. There were no significant differences in the presence of EPS symptoms between patients with recommended doses and those with higher doses of olanzapine.
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PMID:D2 receptor occupancy under recommended and high doses of olanzapine: an iodine-123-iodobenzamide SPECT study. 1156 32

Disruption of prepulse inhibition (PPI) of acoustic startle in rats has been widely used as an animal model for the sensorimotor gating deficit state usually found in schizophrenia. PPI was reported to be regulated by forebrain circuits, including mesolimbic cortex, nucleus accumbens, ventral pallidum, thalamus, and pedunculopontine tegmentum nucleus. Phencyclidine or dopamine agonists, which causes psychotomimetic symptoms in humans, disrupts PPI in animals. The ED50 value of the drugs to reverse the phencyclidine-induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D2 receptor of each drug (including atypical antipsychotics). In contrast, the ED50 value of the drugs to reverse the apomorphine-induced PPI disruption was significantly correlated with the affinity for the dopamine D2 receptor (including typical antipsychotics). Thus the drug that antagonizes the disruption of PPI caused by PCP or DA agonists would be a candidate for a therapeutic agent for the sensorimotor gating deficit state in schizophrenic patients. Neural mechanisms underlying the disruption of PPI were reviewed.
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PMID:[Disruption of prepulse inhibition of acoustic startle as an animal model for schizophrenia]. 1121 97

Because dopamine D2 receptors are the primary targets for antipsychotic drugs, including clozapine and quetiapine, and because some studies have found D2 receptors to be elevated in schizophrenia, we examined the mRNA of three forms of the D2 receptor, particularly the new form of the dopamine D2 receptor, D2(Longer), in post-mortem brains from patients who died with schizophrenia. Using quantitative competitive RT-PCR (reverse transcriptase-polymerase chain reaction), the D2(Longer) mRNA was higher in the frontal cortex, compared to control tissues. The mRNA concentration of D2(Long) and D2(Short) was also higher in the frontal cortex, compared to control tissues. Although most of the schizophrenia patients had received different antipsychotic drugs for varying periods of time, the mRNA of D2(Longer), as well as that for D2(Long) and D2(Short), in such medicated tissues was similar to that in a frontal cortex tissue from a patient who had reliably never received antipsychotic drugs. It is possible, therefore, that the elevation of the mRNAs for D2(Longer), D2(Long) and D2(Short) in the frontal cortex may be related to the disease of schizophrenia itself.
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PMID:Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex. 1124 17

To replicate a previously found negative association between the Del allele of the -141C Ins/Del polymorphism in the 5'-promoter region of the dopamine D2 receptor gene (DRD2) and schizophrenia in Japanese subjects and to examine whether this polymorphism is related to the features of antipsychotic drug treatment, we genotyped 94 control subjects and 234 schizophrenic patients. The schizophrenic patients had a significantly lower frequency of the Del allele (p < 0.05). We found a non-significant trend towards a higher frequency of the Del allele in schizophrenic patients susceptible to neuroleptic-induced extrapyramidal symptoms. The daily dosage of haloperidol, the steady-state concentration of serum haloperidol per daily dosage, and the recent 1-yr cumulative neuroleptic dosage were lower in patients with the Del/Del genotype than in the other patients. These findings support the view that the polymorphism is associated with schizophrenia in Japanese subjects and provide hints for further attempts to establish the relationship between this polymorphism and the features of antipsychotic drug treatment.
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PMID:Association between a polymorphism in the promoter region of the dopamine D2 receptor gene and schizophrenia in Japanese subjects: replication and evaluation for antipsychotic-related features. 1128 87


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