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 dopaminergic system is one of the most important targets for pharmacological treatment of schizophrenia. Despite substantial work on mechanisms of action, it is not clear which dopaminergic pathways mediate the therapeutic effects of antipsychotic drugs. It has been shown that chronic clozapine, an atypical antipsychotic, decreases dopamine levels in the mesocorticolimbic system but not in the nigrostriatal system. Because tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of dopamine, we studied the effect of chronic clozapine in both dopaminergic systems. We demonstrated a decrease of tyrosine hydroxylase mRNA not only in the ventral tegmental area but also in the substantia nigra, the cell body areas of the mesocorticolimbic and the nigrostriatal systems, respectively. The reduced tyrosine hydroxylase mRNA level in these areas is accompanied by an ample reduction in the tyrosine hydroxylase protein level in their corresponding axonal terminal fields, the nucleus accumbens and the striatum. There was thus discordance between the clozapine-induced decrease of tyrosine hydroxylase mRNA and protein and the absence of an effect on dopamine levels in the nigrostriatal system. It has been suggested that reduced levels of dopamine in the mesocorticolimbic system are required for the antipsychotic effect of the drug. Therefore, the modulation of tyrosine hydroxylase gene expression by clozapine in the mesocorticolimbic system might be necessary for its antipsychotic effect; this effect might be of relevance when considering new atypical agents.
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PMID:Tyrosine hydroxylase mRNA and protein are down-regulated by chronic clozapine in both the mesocorticolimbic and the nigrostriatal systems. 1264 84

A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. The COMT valine allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis.
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PMID:Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. 1265 58

Transgenic technology, especially the use of homologous recombination to disrupt specific genes to produce knockout mice, has added considerably to the understanding of dopamine (DA) neuron develop, survival and function. The current review summarizes results from knockout mice with the target disruption of genes involved in the development of DA neurons (engrailed 1 and 2, lmx1b, and Nurr1), in maintaining DA neurotransmission (tyrosine hydroxylase, vesicular monoamine transporter, DA transporter, DA D2 and D3 receptors) and important for DA neuron survival (alpha-synuclein, glia cell line-derived neurotrophic factor and superoxide dismutase). As alterations in DA neurotransmission have been implicated in a number of human neuropathologies including Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder, understanding how specific genes are involved in the function of DA neurons and the compensatory changes that result from loss or reduction in gene expression could provide important insight for the treatment of these diseases.
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PMID:The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease. 1267 88

This study aimed to test the association of the tyrosine hydroxylase (TH) gene with schizophrenia in the Korean population. 334 patients with schizophrenia and 391 healthy volunteers were included. Intron 1 VNTR polymorphism of TH gene was genotyped using polymerase chain reaction techniques. The genotype and allele distribution between patients and controls were not significantly different. However, the positive score of the Positive and Negative Syndrome Scale (PANSS) was higher in the group expressing the TH10 allele (t = 2.245, p = 0.02), although no significant differences were present in the distribution of age of onset, degree of improvement using Brief Psychiatric Rating Scale (BPRS) change, total PANSS score and negative score. This finding suggests that the TH10 allele may be a liability factor for positive schizophrenia in the Korean population.
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PMID:VNTR polymorphism of tyrosine hydroxylase gene and schizophrenia in the Korean population. 1275 55

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

Antipsychotic drugs require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations in specific neuroanatomical loci are likely involved. Haloperidol-induced changes in gene expression in various brain regions have been observed; however, alterations in distinct neuronal populations have remained elusive. The present study examined changes in gene expression profiles of ventral tegmental area (VTA) and substantia nigra (SN) tyrosine hydroxylase immunopositive neurons following 1, 10 or 21 days of haloperidol administration (0.5 mg/kg/day). Macroarrays were used to study the expression of receptors, signaling proteins, transcription factors and pre- and post-synaptic proteins. Data were analyzed using conventional statistical procedures as well as self-organizing maps (SOM) to elucidate conserved patterns of expression changes. Results show statistically significant haloperidol-induced and time-dependent alterations in 17 genes in the VTA and 25 genes in the SN, including glutamate and GABA receptor subunits, signaling proteins and transcription factors. SOMs revealed distinct patterns of gene expression changes in response to haloperidol. Understanding how gene expression is altered over a clinically relevant time course of haloperidol administration may provide insight into the development of antipsychotic efficacy as well as the underlying pathology of schizophrenia.
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PMID:Time-dependent changes in gene expression profiles of midbrain dopamine neurons following haloperidol administration. 1296 67

The serotonergic and dopaminergic inputs to the corpus striatum in human and non-human primates participate in diverse sensorimotor, cognitive, and affective functions, are implicated in dysfunction in diseases such as Parkinson's disease and schizophrenia, and are targets for many of the drugs used to treat these disorders. Sex differences in the incidence and/or clinical course of these disorders and in the effectiveness of related dopaminergic and serotonergic drug therapies suggest that primate striatal indolamines and catecholamines are also influenced by gonadal hormones. However, while well studied in rats, relatively little is known about precisely how gonadal steroids modulate stratial dopamine and serotonin systems in primates. To begin to address this issue, the present studies explored the effects of ovarian steroids on the serotonergic and dopaminergic innervation densities of the caudate, putamen, and the nucleus accumbens in young adult rhesus monkeys. Using densitometry to quantify immunoreactivity for serotonin and for the catecholamine-synthesizing enzyme tyrosine hydroxylase, innervation densities were compared in identified, functionally specialized striatal subdomains across animals that were either ovariectomized or ovariectomized and supplemented with estradiol and/or progesterone, i.e. in a primate model of surgical menopause, with and without hormone replacement therapy. These analyses revealed clear examples of structure-, hemisphere-, and replacement regimen-specific effects of changes in circulating steroids on the densities of each afferent system examined. Further, the predominantly stimulatory effects observed occurred in striatal areas analogous to those suspected as sites of localized dopamine and/or serotonin compromise in Parkinson's disease and schizophrenia. Thus, the hormone actions identified in this study could hold relevance for some of the sex differences identified in relation to these disorders, including the findings of decreased incidence and/or symptom severity in women that have led to hypotheses of protective effects for estrogen.
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PMID:Ovarian hormone influences on the density of immunoreactivity for tyrosine hydroxylase and serotonin in the primate corpus striatum. 1462 19

Tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, is predominantly expressed in several cell groups within the brain, including the dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, and the noradrenergic neurons of the locus coeruleus. To investigate the regulation of cell type-specific TH expression, we cloned and sequenced a 5.5kb fragment of human genomic DNA immediately 5(') of the TH coding region. This 5(')-flanking region does not contain either a CAAT box or a GC-rich region, but does contain a TATA box and consensus binding sequences for basal (TATA and CRE), and DA neuron-specific (NBRE, Gli, and BBE) transcription factors. Sequence analysis showed low overall homology with the rat and mouse TH promoter regions, with the exception of two high-homology domains, which encompassed -2384 to -2323 and -123 to -65, respectively. Interestingly, these distal and proximal domains contained NBRE, BBE, CRE, and TATA boxes, which are known to play important roles in DA neurogenesis. To further localize the TH promoter region responsible for transcriptional activity, we fused a 3301-bp human TH promoter fragment (-3174 to +127) to a luciferase reporter gene, and used this to assess promoter activity in neuronal and non-neuronal cell lines. Consistent with endogenous TH expression, this promoter construct was active in SH-SY5Y human neuroblastoma cells but not F3 human neural stem cells (NSCs). Deletion analysis of TH promoter/luciferase constructs revealed the presence of the repressor element in -1232 to -1210 upstream of transcription initiation site. While this region repressed 85% of promoter activity when transfected into F3 cells, it was not active in SH-SY5Y cells. These data suggest that the repressor element may play an important role in neuron cell-specific expression of the TH gene. Our results may provide insight into neuronal cell-specific expression of the human TH gene and allow a better understanding of catecholaminergic neuron disorders such as Parkinson's disease and schizophrenia.
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PMID:Cloning and cell type-specific regulation of the human tyrosine hydroxylase gene promoter. 1465 89

The neonatal ventral hippocampal lesion in the rat has been used as a model of schizophrenia, a human disorder associated with changes in markers of dopamine and gamma-aminobutyric acid (GABA) circuits in various regions of the brain. We investigated whether alterations in mRNA markers related to the activity of midbrain dopaminergic and GABAergic neurons are associated with this model. We used in situ hybridization histochemistry to assess expression of mRNAs for dopamine transporter (DAT), tyrosine hydroxylase (TH) and glutamate decarboxylase-67 (GAD67) in the midbrain of adult rats with neonatal and adult ibotenic acid lesions of the ventral hippocampus. Neonatally lesioned rats showed in adulthood significantly reduced expression of DAT mRNA in the substantia nigra and the ventral tegmental area but no changes in the expression of TH and GAD67 mRNAs in these midbrain regions. Adult lesioned rats showed no changes in the expression of any of these genes. As the neonatal ventral hippocampal lesion reproduces many aspects of schizophrenia and is used as an animal model of this disorder, these results suggest that the reduction in DAT mRNA could result from developmental neuropathology in the ventral hippocampus and may thus represent a molecular substrate of the disease process.
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PMID:The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain. 1465 5

Dopamine (DA) neurons degenerate in Parkinson's disease and dopamine neurotransmission may be affected in psychotic states seen in schizophrenia. Understanding the regulation of enzymes involved in DA metabolism may therefore lead to new treatment strategies for these severe conditions. We investigated mRNA expression of the cytosolic aldehyde dehydrogenase (ALDH1), presumably involved in DA degradation, by in situ hybridization in DA neurons of human postmortem material. Parallel labeling for GAPDH, neuron-specific enolase, tyrosine hydroxylase, dopamine transporter, and dopamine beta-hydroxylase was used to ensure suitability of tissue specimen and to identify all dopamine neurons. ALDH1 was found to be expressed highly and specifically in DA cells of both substantia nigra (SN) and the ventral tegmental area (VTA) of controls. A marked reduction of ALDH1 expression was seen in surviving neurons of SN pars compacta but not of those in the VTA in Parkinson's disease. In patients suffering from schizophrenia we found ALDH1 expression at normal levels in DA cells of SN but at significantly reduced levels in those of the VTA. We conclude that ALDH1 is strongly and specifically expressed in human mesencephalic dopamine neurons and that low levels of ALDH1 expression correlate with DA neuron dysfunction in the two investigated human conditions.
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PMID:ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia. 1467 78


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