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)

The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D(2)-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[(18)F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activity of DOPA decarboxylase (DDC) (k(D)(3), min(-1)) in the brain of nine unmedicated patients with schizophrenia, first in the untreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline and after treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude of k(D)(3) in both caudate and putamen following 5 weeks of haloperidol therapy. In addition, the magnitudes of k(D)(3) in cerebral cortex and thalamus were also decreased. Psychopathology as measured with standard rating scales improved significantly in all patients. The decrease of k(D)(3) in the thalamus was highly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidol decreased the activity of DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect of chronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons. We link an alteration in cerebral catecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.
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PMID:Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo. 1265 26

The human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC, the second-step monoamine synthesizing enzyme, =DDC: dopa decarboxylase), but not for tyrosine hydroxylase (TH, the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH, the first-step serotonin synthesizing enzyme) (Neurosci Lett 232 (1997) 111-114). These AADC (+)/TH (-)/TPH (-) neurons are named as D-neurons (Jaeger CB, Ruggiero DA, Albert VR, Joh TH, Reis DJ. Immunocytochemical localization of aromatic-L-amino acid decarboxylase. In: Bjorklund A, Hokfelt T, editors. Classical transmission in the CNS, Part I, Handbook of chemical neuroanatomy, vol. 2. Amsterdam: Elsevier, 1984. pp. 387-418). The nucleus accumbens is one of the brain regions that is involved in the pathogenesis of schizophrenia. We examined the distribution of striatal D-neurons using AADC immunohistochemistry and postmortem brains obtained by legal and pathological autopsies (nine controls (27-75 years old) and nine schizophrenics (32-78 years old), postmortem interval to fixation (PMI): 2-30 h). Because the number of AADC-positive neurons per section had a tendency to reduce in the case with longer PMI, we analyzed specimens of five controls (27-64 years old) and six schizophrenics (51-78 years old) in which the PMI was less than 8 h. The number of AADC-positive neurons was reduced in the striatum of schizophrenics compared to that of controls. The reduction was significant in the nucleus accumbens (P<0.05, t-test). D-Neurons might be involved in the pathogenesis of schizophrenia. Further studies using sex-, age- and PMI-matched controls are essential.
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PMID:Number of striatal D-neurons is reduced in autopsy brains of schizophrenics. 1293 95

The human striatum, especially its ventral part, the nucleus accumbens (Acc), contains numerous nonmonoaminergic aromatic L-amino acid decarboxylase (AADC) [=dopa decarboxylase (DDC)] neurons (D-neurons). AADC is the second-step synthesizing enzyme for monoamines and is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by taking up monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. Although previous studies have shown that AADC activity was elevated in the striatum of drug-naive schizophrenia, the number of striatal D-neurons was reduced in autopsy brains of schizophrenia. It is unclear whether or not such reduction of striatal D-neurons implies downregulation. Possible pluripotentiality of D-neurons, including compensatory functions against aging and degeneration, was discussed based on recent published works.
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PMID:Significance of human striatal D-neurons: implications in neuropsychiatric functions. 1509 49

Several lines of evidence suggest that dysfunctions of neurotransmitters are associated with schizophrenia. DOPA decarboxylase (DDC) is an enzyme involved directly in the synthesis of dopamine and serotonin, and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered a candidate gene for schizophrenia. We performed an association study between three single nucleotide polymorphisms in the DDC gene and paranoid schizophrenia. However, in our study no significant differences were found in the genotype distributions and allele frequencies between 80 paranoid schizophrenics and 108 controls for any of the polymorphisms. Neither did the haplotypes of the single nucleotide polymorphisms show any association with paranoid schizophrenia. Therefore, we conclude that the polymorphisms studied do not play a major role in paranoid schizophrenia pathogenesis in the population investigated.
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PMID:No association between polymorphisms in the DDC gene and paranoid schizophrenia in a northern Chinese population. 1531 31

The dopaminergic system has been previously associated to behavioral facilitation and aggression, hence making the pathway a good candidate for suicidal behavior. We studied gene variants in the tyrosine hydroxylase (rs3842727, rs6356) and DOPA decarboxylase (rs1451371, rs1470750, rs998850) genes in a sample of 571 individuals consisting of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide and 312 German control subjects. TH variants were not associated with suicide (uncorrected P = 0.023) and related traits. Some marginal associations could be observed for DDC with suicide, violence, anger, and aggression. In conclusion, our study does not support the involvement of TH gene variants as major contributors to suicide, whereas DDC variants could mediate some features related to suicide and be involved in violent suicidal behavior.
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PMID:Dopa decarboxylase and tyrosine hydroxylase gene variants in suicidal behavior. 1794 5

Many neurobiochemical studies show abnormalities within dopaminergic neuropathways, particularly altered dopamine transmission in etiopathogenesis of mental disorders. Evaluation of genes associated with the dopaminergic system include five well known subtypes of dopaminergic receptors, dopamine transporter and enzymes associated with the synthesis and degradation of dopamine, such as tyrosine hydroxylase, dopa decarboxylase, monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). None of these genes is 'a' pathognomonic factor of schizophrenia onset. In each sequence of the following genes 'a' functional polymorphism can occur. The polymorphisms of genes MAO-A and COMT have been described in relation to various expression or altered activity of these enzymes, their influence on cognitive functions, affective and anxiety disorders, learning disabilities, aggressive behaviour, eating disorders or gender differences.
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PMID:[Genetic polymorphism of COMT in mental disorders]. 1804 78

There is current interest in understanding genetic influences on both healthy and disordered brain function. We assessed brain function with functional magnetic resonance imaging (fMRI) data collected during an auditory oddball task--detecting an infrequent sound within a series of frequent sounds. Then, task-related imaging findings were utilized as potential intermediate phenotypes (endophenotypes) to investigate genomic factors derived from a single nucleotide polymorphism (SNP) array. Our target is the linkage of these genomic factors to normal/abnormal brain functionality. We explored parallel independent component analysis (paraICA) as a new method for analyzing multimodal data. The method was aimed to identify simultaneously independent components of each modality and the relationships between them. When 43 healthy controls and 20 schizophrenia patients, all Caucasian, were studied, we found a correlation of 0.38 between one fMRI component and one SNP component. This fMRI component consisted mainly of parietal lobe activations. The relevant SNP component was contributed to significantly by 10 SNPs located in genes, including those coding for the nicotinic alpha-7 cholinergic receptor, aromatic amino acid decarboxylase, disrupted in schizophrenia 1, among others. Both fMRI and SNP components showed significant differences in loading parameters between the schizophrenia and control groups (P = 0.0006 for the fMRI component; P = 0.001 for the SNP component). In summary, we constructed a framework to identify interactions between brain functional and genetic information; our findings provide a proof-of-concept that genomic SNP factors can be investigated by using endophenotypic imaging findings in a multivariate format.
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PMID:Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA. 1807 79

Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org).
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PMID:Mutations in human monoamine-related neurotransmitter pathway genes. 1844 57

[(18)F]Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson's disease. Following intravenous FDOPA injection, the decarboxylated metabolite [(18)F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons; reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood samples are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [( 18)F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson's disease and schizophrenia.
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PMID:PET studies of cerebral levodopa metabolism: a review of clinical findings and modeling approaches. 1979 23

Presynaptic dopamine (DA) transmission has been measured in schizophrenia using different paradigms aimed at providing estimates of the integrity or the activity of the presynaptic dopaminergic neuron. RESEARCHERS HAVE MEASURED: (1) DA synthesis capacity with [(18) F]DOPA, a measure of the activity of dopa decarboxylase, (2) DA release with studies measuring the impact of a DA releasing stimulant challenge on the binding of a D(2) receptor radiotracer, (3) D(2) baseline occupancy by DA, a measure of baseline intrasynaptic DA, assessed by the changes in binding of D(2) radiotracer induced by DA depletion, and (4) the DA and the vesicular monoamine transporters, to assess the integrity of presynaptic terminals. The relationship between DA release and D(2) receptor occupancy at baseline by DA has also been assessed in the same patients. Overall, these different imaging modalities have converged to show a dysregulation of presynaptic dopaminergic activity in schizophrenia, leading to excessive DA release in the striatum, particularly in the projection to the associative striatum, an area of integration between cognitive and limbic cortical inputs. Excessive striatal presynaptic DA is linked to the emergence of acute psychotic symptoms and to their response to treatment in schizophrenia. Understanding the etiology of this dysregulation and its consequences on the rest of the circuitry is important for future drug development.
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PMID:Presynaptic dopamine in schizophrenia. 2119 51


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