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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in psychopharmacology and neuroscience have brought into view a wide field of competing mechanisms for the etiology of schizophrenia including, but not limited to, deficits in one or more neurotransmitters (dopamine, serotonin, GABA, glutamate, and noradrenaline systems), neurodevelopmental defects in cortical connectivity, and viral infection. Genetic studies suggest heterogeneity in the illness, with multifactorial inheritance. Since cerebral metabolic activity reflects regional brain work for all neurotransmitter systems, imaging studies can provide information on the functional neuroanatomy of a deficit in the individual patient, allowing the grouping of patients for more intensive investigation in more homogeneous groups. Metabolic imaging studies allow psychopharmacological response to be regionally assessed and clinical responders to be identified, even for medications that affect more than one neurotransmitter system or have clinical effects that derive from changes in activity one synapse or more removed from the site of primary action.
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PMID:Positron emission tomography studies of abnormal glucose metabolism in schizophrenic illness. 758 18

A number of factors have been proposed as being linked to schizophrenia: genetic, psychological, endocrinological, metabolic, environmental, virological, and auto-immunological factors, as well as neurotransmitter systems and structural disorders of the brain. All may act as predisposing, triggering, or functionally modulating factors in what probably a condition composed of several types of disorder with varying aetiology. Neuroanatomical and neuromorphological data have revealed ventricular enlargement and diminished frontal and temporal lobe volume in some patients. These changes are concentrated particularly in the hippocampus/parahippocampal gyrus/amygdala, but are relatively small and span some overlap with healthy subjects. Twin studies suggest that at least some of these changes may result from other than genetic factors. Functional disturbances of the brain have also been connected with frontal and temporal structures in some schizophrenic patients. Of the single neurotransmitter substances, dopamine and serotonin appear to represent some of the central restitutive mechanisms whose function is to maintain mental stability; the understanding of their interplay with other neurotransmitters such as noradrenaline, acetylcholine, GABA, and glutamate, should provide a more integrated view of both normal and disturbed brain function.
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PMID:Biological factors in schizophrenia. Structural and functional aspects. 791 12

Electrophysiological and neurosurgical lesion studies with experimental animals have implicated the ascending dorsal noradrenergic bundle of the locus coeruleus system in cognitive process such as memory, learning and selective attention. However, it has also been suggested that noradrenaline (norepinephrine) is crucial in certain cognitive functions associated with the frontal lobes, particularly the prevention of distractibility by irrelevant stimuli. The alpha 2-receptors of the prefrontal cortex appear to be of particular importance in this respect. Studies with humans and experimental primates provide substantial support for this view. The aged primate brain is prone to degeneration of the locus coeruleus, as well as profound catecholamine depletion in the prefrontal cortex, and so is ideal for psychopharmacological investigation of the role of noradrenaline in frontal lobe function. Elderly monkeys show deficits in performance of the delayed response task, which can be reversed directly by both the mixed alpha 1/alpha 2-agonist clonidine, the more specific alpha 2-agonist guanfacine and also, indirectly, by the alpha 2-antagonist yohimbine. It is suggested that these results can be explained by an attenuation of the distracting properties of irrelevant stimuli following stimulation of noradrenergic activity. Conversely, distractibility is magnified whenever noradrenergic activity is reduced. This is supported by similar findings in psychopharmacological studies of healthy humans. The exception to this is when the locus coeruleus is likely to be firing, e.g. in times of stress or when novel stimuli are encountered. Clonidine attenuates locus coeruleus firing on such occasions, and so counteracts any beneficial (or deleterious) effects of stress on task performance. alpha 2-Adrenoceptor agents have little therapeutic value in patients with dementia of the Alzheimer's type. However, they may have some clinical use in patients who have a cognitive symptomatology similar to that of patients who have received neurosurgical excisions to the frontal lobes, e.g. deficits in working memory, executive function or focused attention, with relative sparing of episodic short term memory. Patients with Korsakoff's disease, attention deficit disorder or schizophrenia may benefit from treatment with alpha 2-agents. In particular, idazoxan has putative therapeutic effects in patients with a neurodegenerative disorder, namely dementia of frontal type.
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PMID:Pharmacological manipulations of the alpha 2-noradrenergic system. Effects on cognition. 798 83

The hypothesis is presented, based on the chemical structure of neuromelanin, that one of its functions in the catecholamine neurons in the brain is to protect the cell against toxic quinones (such as dopaminchrome and noradrenochrome, or their dihydroxy isomers) produced from the catecholamines dopamine and noradrenaline (and possibly adrenaline) during the course of prostaglandin synthesis by the enzyme prostaglandin H synthetase, or possibly by spontaneous oxidation. One aminochrome-adrenochrome-has been shown to be neurotoxic and to have psychotomimetic properties in humans. Depending on the site of production these compounds may be involved in the pathogenesis of Parkinson's disease or schizophrenia.
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PMID:On the functional of neuromelanin. 863 29

The action of bright light (2600-2800 lux) on the catecholamine (CA) excretion was analyzed in patients with anxious (11) and melancholic (12) depressions resultant from manic-depressive psychosis and schizophrenia. The melancholic depressed patients were characterized by decreased noradrenaline (NA) and increased adrenaline (A) levels; in anxious depression NA and A were increased. The light therapy resulted in decrease of A level but NA level remained invariable in melancholic depression. Meanwhile the tendency to normalization of excretion of both CA was observed in anxious patients after light therapy. The contrary alterations in A/NA ratio as well as its considerable individual fluctuations were observed after light therapy. The A/NA ratio after light therapy depended mainly upon the initial A/NA ratio (the higher or lower ratio compared to control value).
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PMID:[The action of high-intensity light on catecholamine excretion in depressive patients]. 867 22

The distribution, molecular structure and role of adenosine A2 receptors in the nervous system, is reviewed. The adenosine A2a receptor subtype, identified in the nervous system with ligand binding, functional studies or genetic molecular techniques, has been demonstrated in the striatum and other basal ganglia structures, in the hippocampus, in the cerebral cortex, in the nucleus tractus solitarius, in motor nerve terminals, in noradrenergic terminals in the vas deferens, in myenteric neurones of the ileum, in the retina and in the carotid body. The A2b receptors have been identified in glial and neuronal cells, and may have a widespread distribution in the brain. Activation of adenosine A2a receptors can enhance the release of several neurotransmitters, such as acetylcholine, glutamate, and noradrenaline. The release of GABA might be either enhanced or inhibited by A2a receptor activation. The A2 receptor activation also modulates neuronal excitability, synaptic plasticity, as well as locomotor activity and behaviour. The ability of A2 receptors to interact with other receptors for neurotransmitters/neuromodulators, such as dopamine D2 and D1 receptors, adenosine A1 receptors, CGRP receptors, metabotropic glutamate receptors and nicotinic autofacilitatory receptors, expands the range of possibilities used by adenosine to interfere with neuronal function and communication. These A2 receptor-mediated adenosine actions might have potential therapeutic interest, in particular in movement disorders such as Parkinson's disease and Huntington's chorea, as well as in schizophrenia, Alzheimer's disease, myasthenia gravis and myasthenic syndromes.
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PMID:Adenosine A2 receptor-mediated excitatory actions on the nervous system. 873 76

After having rapidly recapitulated the various arguments which suggest that meso-subcortical dopaminergic neurons are hyperreactive in the productive form of schizophrenia, we suggest in this article that dysfunction of noradrenergic neurons gives rise to this disorder whether of the productive or deficitary variety. In the specific case of deficitary schizophrenia, noradrenergic transmission appears to be desensitized, most likely following intense and repeated activation. Our results in fact show that activation of noradrenergic neurons inhibits cortical dopaminergic transmission mediated by D1 receptors and enhances the functional role of subcortical dopaminergic neurons. On the basis of these data, the lack of noradrenergic transmission would lead to a cortico/subcortical imbalance in favour of cortical areas. Deficitary schizophrenics would then find themselves stalled in a short-term memory situation without external data they could process. The therapeutic effect of substituted benzamides on negative schizophrenic patients may be explained by the observation that these products increase the release of noradrenaline in the frontal cortex and reactive subcortical dopaminergic neurons by blocking D2-type autoreceptors.
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PMID:[Deficit schizophrenia: from pharmacology to clinical practice]. 876 35

TH is a tetrahydrobiopterin-requiring, iron-containing monooxygenase. It catalyses the conversion of L-tyrosine to L-dopa, which is the first, rate-limiting step in the biosynthesis of catecholamines (dopamine, noradrenaline and adrenaline), the central and sympathetic neurotransmitters and adrenomedullary hormones. The cofactor of TH is tetrahydrobiopterin, which is synthesized from GTP in three steps. The TH gene consists of 14 exons only in humans and 13 exons in animals. Human TH exists in four isoforms (hTH1-4) that are produced by alternative mRNA splicing from a single gene. A single mRNA and protein corresponding to hTH1 exists in non-primates. Monkey TH exists in two isoforms, corresponding to hTH1 and hTH2. TH activity is regulated in the short term by feedback inhibition of catecholamines in competition with tetrahydrobiopterin, and by activation and deactivation due to phosphorylation and dephosphorylation, mainly at Ser-19 and Ser-40 of hTH1. The multiple TH isoforms in humans and monkeys have additional phosphorylation, resulting in more subtle regulation. In long-term regulation under stress conditions, TH protein is induced. CRE and AP1 in the 5' flanking region of the TH gene may be the main functional elements for TH gene expression. TH may be closely related to the pathogenesis of neurological diseases, such as dystonia and Parkinson's disease, psychiatric diseases, such as affective disorders and schizophrenia, as well as cardiovascular diseases. The TH gene may prove useful in gene therapy to compensate for decreased levels of catecholamines in neurological diseases, for example, for supplementation of dopamine in Parkinson's disease.
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PMID:Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. 882 46

This review describes an attempt to widen the perspective on schizophrenia and to go beyond the dopamine hypothesis. In recent animal experiments corticofugal glutamatergic pathways have emerged as powerful regulators of a variety of subcortical mechanisms, where the dorsal and ventral striatum appear to play a major role in feedback loops controlling a thalamic filter function. These loops appear to be important regulators of wakefulness and psychomotor activity. A deficient filter function will lead to an overload of sensory input to the cerebral cortex and hyperarousal and may ultimately cause breakdown of the integrative capacity of the cerebral cortex and psychosis. Both negative and positive feedback loops appear to be driven by corticofugal glutamatergic pathways, and deficient functions of these loops may cause or contribute to the positive and negative symptomatology of schizophrenia, respectively. In addition to dopamine and glutamate, several other neurotransmitters, including gamma-aminobutyric acid, noradrenaline, serotonin and acetylcholine, appear to play an important role in psychomotor activity and psychotogenesis. Behavioural and biochemical animal models illustrate the interplay between the various neurotransmitters in these respects.
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PMID:Neurocircuitries and neurotransmitter interactions in schizophrenia. 886 62

Catechol-O-methyl transferase (COMT) metabolizes a variety of catecholamines such as dopamine, adrenaline and noradrenaline. It exists in common high and low activity forms. The low activity form is the result of an amino acid substitution (val-108-met) which reduces the thermostability of the enzyme [Lotta et al. (1994) Biochemistry, 34, 4202-4210]. We have genotyped this polymorphism in 178 trios consisting of Han Chinese schizophrenic subjects and their parents in order to test the hypothesis that the high activity allele is transmitted more often to affected subjects. The data were analysed using the transmission disequilibrium test (TDT), a robust method of detecting linkage in the presence of allelic associations. Of the 131 parents heterozygous at this locus, 80 transmitted the high activity allele (val-108) to affected offspring, while the remaining 51 transmitted the low activity allele (p = 0.005, one-tailed). Combining this result with that of a previous TDT study of the same polymorphism in familial schizophrenia [Kunugi et al. (1996) submitted] gives significant evidence for linkage disequilibrium (p = 0.0015). However, val-108 is frequent in the Han Chinese population, and in the present sample, 239 of the 350 non-transmitted parental alleles were val-108 (68%). It is therefore unlikely that val-108 allele of COMT has a major effect on susceptibility to schizophrenia. Our results suggest that either val-108 is a minor risk factor for schizophrenia, that the COMT gene has additional polymorphisms with greater effect on risk, or that this region of chromosome 22 contains a susceptibility gene which is in linkage disequilibrium with the COMT gene.
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PMID:Preferential transmission of the high activity allele of COMT in schizophrenia. 890 89


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