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)

Dopamine receptor dysfunction and altered tyrosine hydroxylase activity have both been implicated in the pathophysiology of schizophrenia. Schizophrenic patients and control subjects were examined for allele frequencies in the tyrosine hydroxylase and dopamine D2 and D4 receptor genes. No significant differences of allele or genotype frequencies were found between the two groups after adjustment for multiple comparisons. Neither were any significant relationships observed between allele frequencies and a number of clinical variables within the schizophrenic subsample. When no adjustment was made for multiple testing a few significant tendencies were obtained which warrant further research in extended patient and control materials. The results are compatible with the view that the tyrosine hydroxylase, dopamine receptor D2 and D4 gene polymorphisms examined are not of major importance in the aetiology or pathophysiology of schizophrenia.
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PMID:A search for association between schizophrenia and dopamine-related alleles. 890 11

Dopamine is a neurotransmitter in both central and peripheral nervous system. In the central nervous system dopamine is involved in regulation of: movements, emotional processing of sensory input, appetite, vomiting and secretion of anterior pituitary hormones. The most important peripheral effect of dopamine is control of splanchnic and renal blood flows. There are five subtypes of dopamine receptors. D1 receptors are responsible for majority of peripheral dopamine effects; in the brain they modulate activity of limbic system. Symptoms of schizophrenia are produced by increased activation of D2 and D4 receptors. On the other hand, Parkinson's syndrome could be induced by D2 receptors blockade. D3 receptors decrease craving in drug-dependent laboratory animals. Although D5 receptors were found in many brain regions and in peripheral blood lymphocytes, their functions remain unknown. Linking dopamine receptor subtypes with actual effects of dopamine will enable more selective therapy of disorders caused by malfunction of this important system.
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PMID:[Dopamine receptor subtypes]. 892 44

Dopamine (DA) D2 receptors which act by modulating second messenger pathways that include protein kinase C (PKC) and adenylate cyclase (AC) have been repeatedly shown to be increased in striatum from subjects with schizophrenia. Therefore it seemed possible that chronic up-regulation of DA-D2 receptors in the schizophrenic brain could result in a change in either of these two proteins. Hence we measured PKC and AC in striatum from 20 schizophrenic subjects and 20 non-schizophrenic subjects by quantitative autoradiography and could show no difference in the density of either PKC (436 +/- 35 vs. 485 +/- 29 fmol/mg tissue equivalents (TE), mean +/- SEM) or AC (77 +/- 9 vs. 80 +/- 7 fmol/mg TE) in the tissue from schizophrenic compared to the non-schizophrenic subjects. Thus, these data do not support the hypothesis that PKC or AC are changed in the schizophrenic brain.
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PMID:Neither protein kinase C nor adenylate cyclase are altered in the striatum from subjects with schizophrenia. 895

Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson's disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of changes in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson's disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurological parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. Through the parallel development of new radiotracers, kinetic models and better instruments, PET technology is enabling investigation of increasingly more complex aspects of the human brain dopamine system. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research.
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PMID:PET evaluation of the dopamine system of the human brain. 896 6

Dopamine receptors have long been implicated in the etiology of schizophrenia. It has been reported an association of schizophrenia with homozygosity at the dopamine D3 receptor gene locus. We have investigated the distribution of a D3 receptor gene polymorphism (BalI) in 107 schizophrenic Spanish patients and 100 healthy matched controls. No statistically significant differences between the patients and control group were detected with respect to either allele frequencies or genotype distribution. However, if not corrected for multiple testing, a correlation was found between homozygosity and early age of onset of schizophrenia (chi 2 = 3.1, df = 1, P = 0.03) and between A1 allele frequency and disorganized and undifferentiated schizophrenia (chi 2 = 3.4, df = 1, P = 0.03; chi 2 = 2.7, df = 1, P = 0.05, respectively). These results suggest the possibility that D3 polymorphisms may be among the physiological factors underlying schizophrenia; though not the determining factor.
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PMID:Homozygosity at the dopamine D3 receptor gene in schizophrenic patients. 899 15

The DA hypothesis of schizophrenia is one of the oldest biological hypotheses of schizophrenia with many revised versions. However, it is unlikely that any single neurotransmitter hypothesis is able to explain the biological basis of such a highly heterogenous disorder as schizophrenia in a satisfactory way. Rather, it is evident that the biological vulnerability factors and the 'acute neurophysiology' of schizophrenic symptoms involve a complex set of imbalances of aberrant connections in neuronal circuits in the brain. Dopamine is likely to be one of the transmitter substances involved, as evidenced by recent neuroimaging studies in neuroleptic-naive schizophrenia. Regardless of whether the DA hypothesis of schizophrenia is true or not, the DA hypothesis of neuroleptic drug action still has a relatively solid basis. The DA D2 receptor blockade remains the best characterized clinically useful mechanism of drug action to alleviate psychotic symptoms. The ongoing and future work on the precise role of DA in schizophrenia should focus on first-episode/admission neuroleptic-naive schizophrenic patients. Such studies represent the best opportunity of finding out specific changes in the dopaminergic pathways and relating them in a meaningful way to various dimensions of psychopathology seen in schizophrenic patients.
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PMID:Dopamine in schizophrenia. 901 15

Recent advances in molecular neurobiology led to a new understanding on mammalian brain dopaminergic system which play a major role in the regulation of motor, cognitive, emotional, neuroendocrine function as well as in the pathogenesis of several pathological conditions, including neurodegenerative diseases, affective disorders, schizophrenia, drug addiction etc. Functional, biochemical and pharmacological heterogeneity of dopamine receptors, which were divided into D1-like (D1 and D5 subtypes) and D2-like (D2, D3 and D4) families of receptors has been postulated. The article reviews the recent advances including author's own results concerning the structure and function of main dopaminergic brain system, i.e. nigrostriatal and mesolimbic. The problem of autoreceptor regulation of dopaminergic neurotransmission, particularly, the processes of dopamine synthesis, release and metabolism has been specially discussed. An involvement of D2 and D3 dopamine autoreceptors in the control of these processes and differences in the mode of action of typical and atypical neuroleptics demonstrating various affinities to D2 and D3 dopamine receptors are analysed in detail. Dopamine and its metabolites have been determined on freely moving rats using brain microdialysis and high performance liquid chromatography. It is hypothesized that dopamine D3 autoreceptor is preferentially involved in the regulation of dopamine release while D2 one is responsible for the control of dopamine synthesis and metabolism in rat basal ganglia in vivo.
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PMID:[The brain dopaminergic systems: receptor heterogeneity, functional role and pharmacological regulation]. 901 22

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gj mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as pre-proenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or showing increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the receptors mediate.
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PMID:Dopamine receptors and brain function. 902 98

Dopamine D3 receptors have been implicated in pathophysiological substrates of schizophrenia, and neuroleptic drugs which are antagonists primarily at D2 receptors possess therapeutic activity in this disorder. In the present study, rats tested for hypomotility induced by 7-hydroxy-DPAT (7OH, a selective D3 agonist) were pretreated with the neuroleptic haloperidol. These animals showed an attenuated agonist-induced suppression of behavior compared with rats receiving 7OH alone. The drug combination also 'normalized' dopamine metabolism in the frontal cortex, as turnover ratios which are typically enhanced by acute neuroleptic administration were no longer significantly increased when 7OH was also given. These observations suggest that the effects of haloperidol in cortical regions regulating limbic locomotor systems may be important for therapeutic efficacy in schizophrenic symptoms generated from a D3 substrate.
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PMID:Acute haloperidol attenuates the hypomotility induced with 7-hydroxy-DPAT. 910 33

Dopamine-glutamate interactions within discrete neural circuits are increasingly recognized as potential substrates for dysregulation in schizophrenia, and as a result, potential targets for pharmacological intervention in this illness. We examined the regulation, by haloperidol (2 mg kg-1 day-1) and clozapine (20 mg kg-1 day-1), of the mRNAs encoding the four AMPA receptor subunits (gluR1-gluR4), three low-affinity kainate receptor subunits (gluR5-gluR7), and two high-affinity kainate subunits (KA1 and KA2) in the rat hippocampal formation and associated entorhinal cortex. A complex and differential pattern of AMPA and kainate subunit mRNA regulation by clozapine and haloperidol was observed in this study. Both drugs caused significant alterations of most of these mRNAs, but in a heterogeneous and region-specific fashion. These data suggest that these antipsychotic drugs alter the expression of the genes encoding the subunits that express ionotropic glutamate receptors. Given the importance of glutamatergic mechanisms and the hippocampal formation in schizophrenia, these data suggest a potential substrate for neurotransmitter dysregulation in this illness, as well as a potential target for therapeutic intervention.
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PMID:Differential regulation of hippocampal AMPA and kainate receptor subunit expression by haloperidol and clozapine. 911 9


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