Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of amino acid transport across the blood-brain barrier as the limiting factor in the metabolism of monoamines has been emphasized by many recent publications. Particularly critical is the transport of tryptophan, since tryptophan hydroxylase is not saturated. This transport is regulated by complex mechanisms, both at the periphery (total and free plasmatic levels and levels of the other essential amino acids) and centraly (by feedback mechanism initiated at the pre- and post-synaptic levels). The hydroxylated derivatives of tryptophan and tyrosine, i.e. 5-HTP and L-DOPA, most probably share the same transport mechanism as these amino acids themselves. In manic-depressive patients, the uptake of L-5-HTP is increased during the depressive phase, while the uptake of L-DOPA, is increased during the manic phase. We suggest that an increase in the uptake of tryptophan may set off oscillations in all the monoaminergic systems, thus providing a biochemical model of manic-depressive psychosis. In terms of this model, melancholy would be due to a hyperserotoninergic syndrome together with a relative hypocatecholaminergic syndrome. Mania would be due to a homogeneous hypercatecholaminergic syndrome together with a relative hyposerotoninergic syndrome. Such a model is compatible with present knowledge of the physiology of monoamines, of the semeiology and biological disturbances of manic-depressive psychosis, and of the treatment of this disease. It reconciles the monoaminergic and ionic theories of the disease better than other existing hypotheses. A reduced transport of tryptophan with a secondary increase in the transport ot tyrosine provides a conceivable model for schizophrenia. Indeed, a serotoninergic hypoactivity coupled with a dopaminergic hyperactivity, with or without a noradrenergic deficiency, would account for the semeiology quite adequately. This model too would be compatible with present knowledge of monoamine physiology, of the biochemical disturbances underlying schizophrenia and of the mode of action of anti-psychotic drugs. This unitarian heuristic concept of the monoaminergic psychoses would be in better agreement with the classic clinical data concerning this disease (typology intermediate syndromes and crossed heredity).
 ...
PMID:[Hypothetical concept: the physiopathological entity of monoaminergic psychoses]. 108 12

Subregional distributions of serotonin1A receptors and serotonin transporters within the human dorsal raphe nucleus (DR) were determined by quantitative autoradiographic analyses of radioligand binding in tissue sections. [3H]8-Hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT) and [3H]paroxetine were used to label, respectively, serotonin1A receptors and serotonin transporters in the subnuclei of the DR, which were delineated on the basis of tryptophan hydroxylase (TrpOH) immunoreactivity. [3H]8-OH-DPAT binding was coextensive with the TrpOH-immunoreactive cell bodies and fibers but was distributed unevenly among the subnuclei. In contrast, [3H]paroxetine binding was present throughout the central gray matter, with relatively homogeneous labeling across the subnuclei of the DR. In rostral sections, [3H]8-OH-DPAT binding (fmol/mg protein) in the dorsal subnucleus was lower than that in the ventral or the interfascicular subnucleus. Within the interfascicular subnucleus, [3H]8-OH-DPAT binding decreased progressively in a rostral-to-caudal fashion. The highest levels of [3H]8-OH-DPAT binding were found in the ventrolateral subnucleus at the level of the caudal extent of the trochlear nucleus. The influence of age and postmortem interval on radioligand binding was also examined. These data in the human DR indicate that serotonin1A receptors are differentially distributed among the subnuclei and along the rostro-caudal axis of the midbrain raphe, and serotonin transporters appear to be relatively evenly distributed throughout the DR. Subregional analyses of such serotonergic markers may prove useful in evaluating the role that serotonin may play in depression, schizophrenia, and suicide.
 ...
PMID:Quantitative subregional distribution of serotonin1A receptors and serotonin transporters in the human dorsal raphe. 884 77

Studies in the past have revealed serotonin to play a role in regulating the development and maturation of the mammalian brain, largely through the release of the astroglial protein S-100beta. S-100beta plays a role in neurite extension, microtubule and dendritic stabilization and regulation of the growth associated protein GAP-43, all of which are key elements in the production of synapses. Depletion of serotonin, and thus of S-100beta, during synaptogenesis should lead to a loss of synapses and the behaviors dependent on those synapses. The current study was undertaken to test this hypothesis. In order to assess the influence of serotonin we have looked at the synaptic density in the adult after depletion, by using immunodensitometry of synaptic markers (synaptophysin and MAP-2) and by studying behaviors thought to be highly dependent on synaptic plasticity and density. Male Sprague-Dawley rats were depleted of serotonin on postnatal days (PND) 10-20 by treating with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA; 100 mg/kg, s.c.). On PND's 30 and 62, animals were perfused for immunodensitometry. Littermates were used for behavioral testing. At PND 55-62, the animals were tested in an interchangeable maze with olfactory cues and in an eight-arm radial maze. Our results show a loss of both synaptic markers in the hippocampus on PND 30. At PND 62, the only remaining loss was of the dendritic marker MAP-2. The animals had deficits in both behaviors tested, suggestive of spacial learning deficits and of the failure to extinguish learned behaviors or to re-learn in a new set. Our findings show the long-term consequences of interfering with the role of serotonin in brain development on the morphology and function of the adult brain. These findings may have implications for human diseases, including schizophrenia, thought to be related to neurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure. Moreover, they provide further insights into the functioning of serotonin and S-100beta in development and aging.
 ...
PMID:Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits. 923 19

We determined allele frequencies for polymorphisms at several loci of interest in neuropsychiatry-tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), ciliary neurotrophic factor (CNTF), and the mu opioid receptor (OPRM1)-in samples of individuals from populations in several different parts of the world. Associations with psychiatric illness have been proposed for specific polymorphisms at TPH (suicide-related behaviors and impulsivity), DRD3 (schizophrenia and bipolar affective disorder), SLC6A3 (susceptibility to cocaine-induced paranoia and attention-deficit disorder), CNTF (psychosis), and OPRM1 (substance dependence). APOE alleles are related to risk of Alzheimer disease. We found significant allele frequency variation among populations at all six loci. These results will provide a global framework of normal variation at these loci that might have functional significance or otherwise be related to susceptibility to various disorders or behavioral phenomena. Knowledge of this variation can be important for study design and data interpretation when individuals from various population groups are research subjects and may eventually help lead to a better understanding of behavioral adaptation.
 ...
PMID:Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), mu opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)). 979 Jul 47

Serotonin is a key neurotransmitter in the central nervous system, and dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex psychiatric diseases. Polymorphisms of many of the genes involved in serotonin biosynthesis, catabolism, and response have been reported, suggesting that genetic variability may underlie the development of diseases such as schizophrenia, obsessive compulsive disorder, and suicide. A number of single-gene polymorphisms in serotonergic pathways have been examined in these and other diseases, but to date results from this candidate gene approach have been disappointing. Although this may be because the detection of a small effect may require the analysis of large numbers of patients and controls, an alternative explanation is that the clinical importance of a single subtle genetic variant may be overlooked unless other functionally related genes are studied in tandem. To facilitate an integrated analysis, we have developed a PCR-SSP-based assay that permits the simultaneous genotyping of 13 single nucleotide polymorphisms in 9 serotonergic genes under identical conditions. These genes include tryptophan hydroxylase, tryptophan dioxygenase, monoamine oxidase A, and the serotonin receptors 5HT1A, 5HT1D-alpha, 5HT1D-beta, 5HT2A, 5HT2C, and 5HT5A. Using this technology, we have genotyped 100 Caucasoid control individuals and demonstrate that this approach is reliable, quick, cheap, and easy to interpret. We anticipate that this will facilitate the analysis of the genetic basis of susceptibility and phenotypic variability of a number of complex psychiatric diseases. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:621-627, 1999.
 ...
PMID:Unified approach to the analysis of genetic variation in serotonergic pathways. 1058 80

Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed.
 ...
PMID:An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder. 1120 46

Associations between schizophrenia and four candidate genes were tested among Indian patients with schizophrenia and their parents (DSM-IV criteria, n = 179 families). Polymorphisms within the genes encoding the serotonin 2A receptor (HT2A), tryptophan hydroxylase (TPH), catechol-O-methyl transferase (COMT) and dopamine transporter (DAT) were thus investigated. Two polymorphisms each were analyzed at HT2A and TPH, enabling haplotype-based analyses using the transmission disequilibrium test (TDT) for these genes. No significant associations were detected. Pooled analysis of samples like ours may be necessary to definitively exclude putative allelic associations at these loci.
 ...
PMID:Family-based association studies of monoaminergic gene polymorphisms among North Indians with schizophrenia. 1131 26

Serotonergic neurotransmission may be involved in the etiology of schizophrenia. We systematically searched for human tryptophan hydroxylase (TPH) coding polymorphisms, and detected a novel pentanucleotide repeat deletion polymorphism (GTTTT)4/5 in TPH intron 1b. We also confirmed A779C intron 7. Neither polymorphism showed a significant association with schizophrenia (182 patients with schizophrenia, 148 controls). A significant association, however, between A779C genotypes and the total Manchester Scale (MS) scores was found in male patients (P = 0.045). Subsequently, a significant association was also found between A779C genotypes and the MS negative symptoms scores in male patients (P = 0.030). These results suggest that the TPH gene may play a role in the negative symptoms in male patients with schizophrenia.
 ...
PMID:Polymorphisms of tryptophan hydroxylase gene and the symptomatology of schizophrenia: an association study. 1132 41

The human tryptophan hydroxylase (TPH) gene, the rate-limiting enzyme in serotonin biosynthesis, was localized on human chromosome 11p14-p15.3. Variation within intron 7 of the TPH gene was found to influence serotonin metabolism in the brain. To explore the possible role of TPH in the pathogenesis of schizophrenic disorders, we genotyped the TPH A218C polymorphism in 196 schizophrenic patients and 251 controls. The results demonstrated that genotype distribution was significantly different between schizophrenic patients and control subjects (P=0.002). No association was found between TPH genotypes and suicidal history in schizophrenic patients (P=0.239). The positive finding in this study suggests that the TPH 218A allele is a risk factor for schizophrenic disorders or is in linkage disequilibrium with the putative schizophrenia susceptibility locus in Han Chinese population.
 ...
PMID:Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders. 1134 64

Disturbances of the serotonergic pathway have been implicated in many psychiatric disorders, including alcoholism, aggression, schizophrenia and depression. The personality dimension of harm avoidance is correlated positively with the activity of mesolimbic serotonergic neurons. The goal of this study was to determine the role of the genes in this pathway in the development of type II alcoholism. A sample of alcoholics and normal controls were screened with the variations in tryptophan hydroxylase (TPH), serotonin receptors (5-HT2A and 5-HT2C), serotonin transporter (5-HTT), and monoamine oxidase A (MAO-A) genes. The results of association studies for type II alcoholics were the most significant with 5-HTT (P = 0.011) and MAO-A (P = 0.029) genes. However, after correction for multiple comparisons, none of the results reached the significance level. These data indicate that the genes in the serotonergic pathway may be involved in the development of type II alcoholism but the gene effects are very small.
 ...
PMID:Serotonergic pathway genes and subtypes of alcoholism: association studies. 1152 23


1 2 3 4 Next >>