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)

We report a null mutation in the first exon of the human dopamine D4 receptor (DRD4) gene. The mutation is predicted to result in a truncated non-functional protein and is the first natural nonsense mutation found in a human dopamine receptor gene. It occurs with a frequency of about 2% in the general population. The distribution of the mutation was found to be similar in healthy controls and patients suffering from psychiatric diseases which included schizophrenia, bipolar affective disorder and Tourette's syndrome, indicating that heterozygosity for this mutation in the DRD4 gene is not causally related to major psychiatric diseases. We also identified an adult male who is homozygous for this mutation. He shows no symptoms of major psychiatric illness, but he displays somatic ailments including acousticous neurinoma, obesity and some disturbances of the autonomic nervous system. Some of these symptoms might be related to the absence of functional DRD4 protein.
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PMID:Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity. 788 21

Sex steroid hormones influence the dopaminergic systems of the hypothalamus as well as the extrahypothalamic regions of the brain in controlling movement and behavior in both humans and animals. This review focuses on the effects of sex steroids on dopaminergic activity in extrahypothalamic brain areas. Among sex steroids, estrogens have been most extensively investigated, and many studies report that estrogens affect behaviors mediated by the basal ganglia, such as in humans suffering from extrapyramidal disorders. Epidemiological and clinical evidence also suggests an influence of estrogens on the vulnerability threshold for schizophrenia and sex differences in the clinical expression of this disease. Clinical observations point to a role of androgenic hormones in Gilles de la Tourette's syndrome. In normal humans, sex steroids were also shown to influence motor and cognitive performance. Biochemical and behavioral studies in animals have also shown the effect of sex steroids on dopaminergic activity in the basal ganglia; however, both activating and inhibiting effects have been reported. This may partly be explained by effects of the dose, duration of treatment, interval between steroid administration and testing the behavior measured, and the part of the basal ganglia from which the behavior is elicited. In view of the numerous variables that influence net dopaminergic response to steroids, focus will be on the literature using similar experimental conditions to assess the effect of in vivo chronic steroid treatment, acute short-term steroid treatment and the estrous cycle as well as in vitro effects of steroids on dopamine receptors. These experimental paradigms point to two general mechanisms of action of steroids: a rapid short-term non-genomic membrane effect and a slower long-term possibly genomic effect of steroids on dopamine systems. Combining dopaminergic drugs with sex steroids could improve efficacy or reduce side effects associated with these drugs. Examples of such combined treatments in rats and monkeys are presented for delta 9-tetrahydrocannabinol, cocaine, neuroleptics, apomorphine and L-DOPA. A better understanding of steroid-dopamine interactions and the possible isolation of conditions to have only pro or anti dopaminergic activity could then be used to develop combined therapies or to optimize drug treatments that would take into account the patient's sex and endocrine status.
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PMID:Modulation of brain dopamine transmission by sex steroids. 801 4

The carrier molecule that transports dopamine (DA) across the synaptic membrane is known as the dopamine transporter (DAT). Depending on the ionic conditions, DAT may function as a mediator of both the inward directed DA transport known as the "reuptake" and the outward directed DA transport known as the "release." The functional significance of DAT is in the regulation of DA neurotransmission by terminating the action of DA in the synapse via reuptake. With use of DAT binding as a presynaptic marker to measure altered DA innervation, abnormalities of the DAT binding have been demonstrated in idiopathic Parkinson's disease, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, and progressive supranuclear palsy. Moreover, the identification of DAT as the neuronal element that mediates the addictive properties of cocaine highlights its significance in cocaine addiction. Cocaine binding in the brain is heterogeneous, and there is an uneven distribution of the high- and low-affinity binding sites across the anatomical regions. Regional differences in ligand binding are observed by using both [3H]cocaine and the diphenyl-substituted piperazine derivatives known as the "GBR series" of ligands. The identification of compounds that inhibit the binding of medications for cocaine abuse. Furthermore, clarification of the various binding domains that may be relevant to transporter function in human neuropsychiatric disorders may lead to the development of new medications for schizophrenia, Tourette's disease, and drug addiction.
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PMID:Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance. 814 55

We have investigated detection thresholds for a foveal blue test light using a Maxwellian view system in 61 normal subjects, 19 patients with Huntington's chorea, 14 patients with Tourette's syndrome, and 20 patients with schizophrenia. Ten measurements were made: The blue test light (1 degree diameter, 500 msec duration) was presented either superimposed on a yellow adaptation field (5 degree diameter) or 500 msec after switching off this field (transient tritanopia effect). In both cases five different background intensities were presented. The only abnormality found was in patients with Huntington's chorea. During adaptation these patients' thresholds are significantly higher than normal (p < 0.005). No change was found in the transient tritanopia effect. Huntington's disease causes degeneration of several different transmitter systems in the brain. Increment threshold testing allows for noninvasive investigation of patients and confirms the involvement of the retina in the degenerative process in Huntington's chorea.
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PMID:Impairment of retinal increment thresholds in Huntington's disease. 821 45

One of the more difficult psychopharmacologic aspects of current clinical psychiatry is finding a neuroleptic drug that adequately treats delusional states. Furthermore, many chronic schizophrenics remain resistant to standard antipsychotic medication, and clozapine is effective in only 30% to 50% of refractory cases. In addition, clozapine has several serious side effects and is expensive. We have determined that pimozide is clearly effective in Tourette's syndrome, maintenance schizophrenia, and some delusional disorders. We further demonstrate that the drug is likely to be effective in the treatment of the negative symptoms of schizophrenia and other delusional states. In addition, we suggest that a trial of pimozide may be indicated before giving clozapine to treatment-resistant schizophrenic patients. The side effect that probably most limits pimozide's current use is the possible production of ECG abnormalities. This side effect does not seem to be a realistic clinical concern, however, if the patients are properly screened and the pimozide dose is maintained at or below 20 mg/day.
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PMID:Clinical uses of pimozide. 845 77

In the present study we sought to identify genetic variation in the 5-HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetic predisposition to neuropsychiatric diseases. Genomic DNA samples from 159 unrelated subjects (including 45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette's syndrome, as well as 25 healthy controls) were investigated by single-strand conformation analysis. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as the 5' untranslated region of the 5-HT1A gene. The region upstream to the coding sequence we investigated contains a functional promoter. We found two rare nucleotide sequence variants. Both mutations are located in the coding region of the gene: a coding mutation (A-->G) in nucleotide position 82 which leads to an amino acid exchange (Ile-->Val) in position 28 of the receptor protein and a silent mutation (C-->T) in nucleotide position 549. The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n = 352) and controls (n = 210) but was found in similar frequencies in all groups. Thus, this mutation is unlikely to play a significant role in the genetic predisposition to the diseases investigated. In conclusion, our study does not provide evidence that the 5-HT1A gene plays either a major or a minor role in the genetic predisposition to schizophrenia, bipolar affective disorder, or Tourette's syndrome.
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PMID:Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene. 854 52

Until recently, Obsessive-Compulsive Disorder (OCD) was considered rare trouble with rather poor outcome. Currently progress in behavioral psychology, psychopharmacology and methodology of epidemiologic studies multiplying by 50 the traditional prevalence rates, give an impetus to the interest in this pathology. Recent clinical and epidemiologic data in OCD are reported in this paper. Multiple questions are evoked such as the issue of OCD homogeneity, the meaning of comorbidity with other psychological disorders: depression, panic attacks, schizophrenia, Gilles de la Tourette syndrome, the reality of OCD prevalence rate in general and psychiatric populations, the usefulness of classical demarcation between psychosis/neurosis in the treatment of OCD, and finally the search for a genetic diathesis and risk factors implicated in predisposition to OCD. A close relationship between clinical, epidemiologic and genetic approaches seems to be required in order to answer these questions and constitutes a first step prior to carrying on basic and applied research.
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PMID:[Obsessive compulsive disorder. Clinical and epidemiologic studies]. 864 Nov 57

The dopamine transporter (DAT) is the carrier protein that transports dopamine across the presynaptic membrane. The DAT terminates the action of dopamine (DA) in the synapse via reuptake and thus regulates DA neurotransmission. The transporter has been studied by direct binding techniques using a variety of ligands which are inhibitors of DA transport. DAT binding, both in vivo (positron emission tomography) and in vitro (post mortem) may serve as a presynaptic marker to measure altered DA innervation in several neuropsychiatric diseases such as idiopathic Parkinson's disease, Tourette's disease, schizophrenia or cocaine addiction. In Parkinson's disease, a reduction in the density of binding sites could be due either to a degeneration of the terminal dopaminergic projections or to a compensatory readjustment in the level of dopamine synaptic transmission. This dopaminergic cell specific marker could also aid in attempts to elucidate the rate at which dopaminergic cells are lost in this disease. MPTP (a neurotoxin which induces a parkinsonian-like syndrome after conversion in MPP+) uses DAT to enter the neuron and exert its toxic effect which may be prevented by pretreatment with DA uptake blockers. In cocaine abuse, DAT mediates the addictive properties of cocaine. Cocaine binding sites on the carrier may be distinct from DA binding sites allowing the development of medication sparing the DA function but impairing the cocaine effects. In schizophrenia, functional DA uptake was reported to be increased in the striatum in post mortem brains, whereas the kinetic parameters of the uptake sites were unchanged using different transporter labeling ligands. Thus, this marker does not provide any evidence for the dopaminergic hypothesis, but an impairment of the DAT itself could possibly be involved in the etiology of schizophrenia. However, the possible interaction of drugs such as L-Dopa or neuroleptic treatment with transporter binding may be taken into account in the results analysis. Finally, the DAT gene is also an important candidate gene for psychiatric diseases such as schizophrenia or cocaine abuse.
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PMID:[The dopamine transporter: characterization and physiopathologic implications]. 867 69

A model for a new approach to neuropsychiatric gene linkage is proposed in the context of increased chromosomal breakage which has recently been reported in association with Tourette syndrome, schizophrenia, Rett syndrome and the psychopathology associated with mentally normal, female obligate fra-X carriers. Chromosomal fragility may be connected with the formation of unstable repeat sequences at multiple sites resulting in a continuum of effects, ranging from advantageous evolutionary changes, to more serious neurobehavioural disorders, with neurodegenerative states on the extreme end of the spectrum. The current major problem with phenotype-genotype correlations in complex neuropsychiatric disorders may, therefore, be due to the distance between a postulated breakage-enhancing effect of the primary gene(s), and the continuum of diverse phenotypes resulting from the secondary-gene involvement at a varying number of fragile sites. A unifying view of behavioural alteration, viewed in anthropogenetic context, rather than a DSM-based reductionist approach may be required for the elucidation of psyche-destabilizing genetic changes.
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PMID:A paradigmatic shift in the approach to neuropsychiatric gene linkage may require an anthropogenetic perspective. 877 Oct 44

This paper aims to explore the influence of the immune system on the pathobiochemistry of movement disorders (Tourette syndrome, obsessive compulsive disorders and attention-deficit disorder, with and without hyperactivity) and schizophrenia. In children, a temporal relationship has been observed between contraction of a group A beta-hemolytic streptococcal infection and subsequent presentation with one of the movement disorders. Pathology investigations reveal that elevated antineuronal antibodies are associated with movement disorders. Similarly, elevations in interleukin-1 beta and interleukin-6 have been reported in schizophrenia. It is now known that the immune system can be activated by conditions other than a viral or bacterial infection, such as: neurological insult, neurotoxicity--endogenous and environmental, neurotransmitter and cholesterol dysregulation. These latter avenues of immune system activation will be explored with respect to schizophrenia.
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PMID:Immunological influences in attention-deficit disorder and schizophrenia; is there a link between these two conditions? 877 Oct 53


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