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

Recent studies have implicated the thalamus as a possible site for neuroanatomical and neurochemical changes in schizophrenia. In the present study, we investigated thalamic neurochemical correlates of behaviors potentially linked to schizophrenia. Whole thalamic DOPAC levels were elevated in rats that had poor extinction of the acoustic startle response. The dopamine agonist apomorphine microinjected into the ventromedial thalamus (VmT) disrupted prepulse inhibition of startle. Catalepsy was induced by VmT microinjections of the GABA-A agonist muscimol. A previous study revealed attentional disturbances and suppression of frontal cortical metabolic activity after muscimol microinjections into the mediodorsal thalamic nucleus. Together with recent findings of neuron cell loss and elevated DA levels in the thalamus of schizophrenics, these data suggest the involvement of disturbances of thalamic neurotransmission in schizophrenia.
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PMID:Startle and sensorimotor correlates of ventral thalamic dopamine and GABA in rodents. 874 49

The authors investigated the presence of a serum activity inhibiting the specific binding of 3H-flunitrazepam (which labels the central benzodiazepine receptors) (BBIA) in patients with different psychiatric disorders and analyzed it by means of high performance liquid chromatography (HPLC) analysis. The results showed that the lowest activity was present in healthy controls who were not different from patients with schizophrenia and obsessive-compulsive disorder. On the contrary, the BBIA values of these 3 groups of patients were significantly lower than those found in patients with bipolar disorder in various phases (depressive, mixed or manic), in unipolar depressives and in patients with panic and delusional disorders. The HPLC analysis of the serum extracts revealed the presence of 3 peaks of activity which were differently distributed in the patients and in the healthy controls, peak 3 being totally absent in the last group and mainly represented in bipolar depressives. The GABA ratio values showed that peaks 1 and 2 behave as agonists while peak 3 behaves as an inverse agonist. The mass fragmentography of the different peaks is in progress.
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PMID:Benzodiazepine binding inhibitory activity: new supportive findings on its presence in psychiatric patients and further biochemical analyses. 888 52

A recent postmortem study has reported that there is a widespread upregulation of GABA(A) receptor binding activity throughout most subregions of the hippocampal formation of schizophrenic brain. The current study has been undertaken to determine whether the benzodiazepine (BZ) receptor, which is a component of the GABA(A) receptor complex, may also be upregulated in schizophrenics. Using a low-resolution film autoradiographic technique to localize [3H]flunitrazepam binding, the subregional and laminar distribution of specific BZ receptor binding was found to parallel that of the GABA(A) site, except in the area dentata where BZ binding was approximately 73% higher in the outer molecular layer. When BZ receptor binding was compared in the same normal control (n = 15) and schizophrenic (n = 8) cases in which the GABA(A) receptor was analyzed, there were very few differences noted between the two groups, except for small, though significant, increases in the stratum oriens of CA3 (30%), the subiculum (20-30%) and the presubiculum (15-20%) of the patient group. These latter increases overlapped with the subregions and laminae in schizophrenics showing the most marked increases of GABA(A) receptor binding. Using a high-resolution technique to evaluate specific BZ receptor binding on different neuronal subtypes, no difference was observed on either pyramidal or nonpyramidal neurons of sector CA3 where GABA(A) receptor activity had been found to be significantly increased on the latter neuronal subtype. The potential confounding effects of age, postmortem interval and exposure to either benzodiazepine or neuroleptic drugs do not account for the lack of marked differences in BZ receptor binding in the schizophrenic group. Taken together, the results of this study are consistent with the possibility that defective GABAergic integration in schizophrenia may be associated with an uncoupling in the regulation of the GABA(A) and BZ receptors.
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PMID:Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain. 916 47

structural abnormalities of the cerebral cortex in schizophrenia have been revealed by magnetic resonance imaging, although it is not clear whether these abnormalities are diffuse or local. We predicted that changes in cortical structure would result in abnormalities in biochemical markers for the glutamate system in post-mortem brain, and that the pattern of neurochemical abnormalities would be a clue to the distribution and extent of pathology. A number of studies have now reported increases in biochemical and other markers of glutamatergic cell bodies and terminals in the frontal cortex in schizophrenia. These findings are consistent with the presence of an abnormally abundant glutamatergic innervation, which may be due to an arrest in the normal developmental process of synaptic elimination. In the anterior temporal cortex and hippocampus there is evidence of an asymmetric loss of glutamate terminals, and of reduced GABA function, which may be secondary to the glutamatergic deficit. Glutamate cell body markers are spared in the temporal lobe; we argue that the loss of glutamate uptake sites may reflect the loss of an extrinsic glutamatergic innervation of the polar temporal cortex which arises from the frontal cortex. These fronto-temporal projections may be vulnerable because they arise from a cytoarchitecture which has not been stabilized by remodelling during early post-natal life. There have been several therapeutic studies of drugs with actions on brain glutamate systems. Based on the glutamate deficiency theories, one approach has been to enhance glutamatergic function using agonists of the N-methyl-D-aspartate-linked glycine site. However, there are no clear therapeutic effects, and some studies report aggravation of positive symptoms. This might be expected if, as part of our post-mortem studies suggested, there is excess glutamatergic innervation in some brain regions in schizophrenia. There is neuropsychological evidence that frontal abnormalities in schizophrenia may be genetically determined. We found that first degree relatives of schizophrenic patients were selectively impaired in tests of frontal lobe function, whereas both frontal and temporal function is impaired in patients We conclude that the genetic predisposition to schizophrenia involves impaired frontal lobe function. Psychotic symptoms develop only when a second process results in a loss of fronto-temporal projections and leads to temporal lobe dysfunction.
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PMID:Familial and developmental abnormalities of front lobe function and neurochemistry in schizophrenia. 925 79

The desire to understand the pathophysiology of schizophrenia has inspired an explosion in research over the past decade. This review highlights some key studies that have led to fundamental changes in our understanding of this disorder, focusing on the search for genes in schizophrenia, as well as several recent alternatives to the original dopamine hypothesis of schizophrenia. Advances in genetic methodology have allowed schizophrenia researchers to conduct genome-wide searches for susceptibility genes. Although these studies have identified several regions that demonstrate potential linkage with schizophrenia, a definitive genetic cause has not yet been proved. Recent neurochemical hypotheses have focused on the cortical amino acid neurotransmitter systems (i.e., glutamate and GABA), while anatomical studies suggesting abnormal brain development and premorbid functional deficits have led some researchers to propose a neurodevelopmental origin for schizophrenia. A sizable database can be marshaled in support of each of these ideas, but none as yet fully explain the biological basis of schizophrenia.
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PMID:The biological basis of schizophrenia: new directions. 926 13

Glutamate and GABA are the principle neurotransmitters of the cerebral cortex and are known to modulate dopaminergic function. Evidence of structural abnormalities in the cortex raises the possibility that schizophrenia involves disturbances of cortical amino-acid neurotransmission. The psychotomimetic effects of phencyclidine, a glutamate antagonist, have been taken to suggest that schizophrenia involves reduced brain glutamate function. Direct evidence for diminished glutamate function in schizophrenia is lacking. However, in polar temporal cortex and hippocampus we reported evidence of an asymmetric loss of glutamate terminals, and of reduced GABA function, which may be secondary to the loss of glutamatergic input. Glutamate cell body markers are spared in temporal lobe; the neurones which degenerate may originate in frontal cortex. A number of studies have reported increases in markers of glutamatergic cell bodies and terminals in orbital frontal cortex in schizophrenia. These findings are consistent with the presence of an abnormally abundant glutamatergic innervation, which may be the result of an arrest in the normal process of cellular and synaptic elimination which occurs during development. There is evidence that frontal abnormalities in schizophrenia are genetically determined. We suggest that glutamatergic abnormalities in anterior temporal cortex in schizophrenia are the result of the degeneration of fronto-temporal projections. Orbital frontal projections to polar temporal cortex may be prone to degeneration because they arise from an unstable frontal cortical cytoarchitecture which has not completed the normal process of post-natal remodelling. The structural abnormality of the orbital frontal region may confer vulnerability to some intrinsic or extrinsic mechanism, which brings about a progressive degeneration of projections to polar temporal lobe.
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PMID:A two-process theory of schizophrenia: evidence from studies in post-mortem brain. 927 90

Limbic cortical regions, including anterior cingulate cortex (ACC), prefrontal cortex (PFC) and entorhinal cortex (ERC), have been implicated in the neuropathology of schizophrenia. Glutamate projection neurons connect these limbic cortical regions to each other, as well as to the terminal fields of the striatal/accumbens dopamine neurons. Subsets of these glutamate projection neurons, and of the GABA interneurons in cortex, contain the neuropeptide cholecystokinin (CCK). In an effort to study the limbic cortical glutamate projection neurons and GABA interneurons in schizophrenia, we have measured CCK mRNA with in situ hybridization histochemistry in postmortem samples of dorsolateral (DL)PFC, ACC and ERC of seven schizophrenics, nine non-psychotic suicides and seven normal controls. CCK mRNA is decreased in ERC (especially layers iii vi) and subiculum in schizophrenics relative to controls. Cellular analysis indicates that there is a decrease in density of CCK mRNA in labelled neurons. In so far as ERC CCK mRNA is not reduced in rats treated chronically with haloperidol, this decrease in schizophrenics does not appear to be related to neuroleptic treatment. In contrast, in DLPFC, where schizophrenics do not differ from normals, the suicide victims have elevated CCK mRNA (especially in layers v and vi), and increased cellular density of CCK mRNA, relative to both normals and schizophrenics. These results lend further support for the involvement of ERC and hippocampus in schizophrenia, suggesting that neurons that utilize CCK may be particularly important. Similarly, an increase in CCK mRNA levels in the PFC of suicides adds to a growing body of evidence implicating this structure in this pathological state. In so far as CCK is co-localized with GABA or glutamate in cortical neurons, both of these neuronal populations need to be studied further in schizophrenia and suicide.
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PMID:Abnormal cholecystokinin mRNA levels in entorhinal cortex of schizophrenics. 927 88

Several kinds of psychiatric symptoms (anxiety, depression, schizophrenia) have been associated with epilepsies, and clinical data suggest that patients with seizures involving limbic structures are the most prone to develop behavioural disorders between the seizures (i.e. interictally). Studying the neurobiological mechanisms that underlie these symptoms is difficult in humans because of different interfering factors (e.g. psychosocial difficulties, pharmacological side-effects, lesions), which can be avoided in animal models. Using repetitive electrical stimulations (kindling) or local applications of a neuroexcitotoxin in limbic structures (mainly the amygdala and hippocampus), several authors have reported lasting changes of emotional reactivity in cats and rats. These changes appear as anxiety-related reactions expressed as a hyperdefensiveness in the cat, or a reduction of spontaneous exploration in tests predictive of anxiogenic effects in the rat. Some neuroplasticity processes known to develop during epileptogenesis (neuronal-hyperexcitability, modulation of GABA/benzodiazepine transmission) may participate in these lasting changes of behaviour, especially in structures involved in the control of fear-promoted reactions (amygdala, periaqueductal grey matter). In addition, endogenous control systems may also play a critical role in the occurrence of interictal behavioural disorders.
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PMID:Anxiogenic-like consequences in animal models of complex partial seizures. 941 1

The largest cluster of positive results, considering both bipolar and schizophrenia, occurs in the 4p region that includes D4S394 and DRD5. Four groups report at least weakly positive linkage analyses this region for bipolar disorder, and two groups find weak positive allelic association with schizophrenia in the region, although at separate markers. On the other hand, at least five groups do not find evidence for linkage of bipolar disorder to this area of 4p. The pattern on 4q is less clear, with a mixture of negative and small positive results in either bipolar or schizophrenia families. Additional allelic association and TDT studies of 4p markers in bipolar disorder and in schizophrenia might be able to narrow the focus of the 4p investigations. The dopamine D5 receptor gene has seductive qualities as a candidate gene because of the pharmacology of psychotic disorders. It would be helpful to have additional markers developed close to or in the recoding region of DRD5 in order to have the extra information at the DNA level provided by haplotype analysis. Chromosome 4 susceptibility loci may figure prominently in alcoholism, although a great deal of work remains to be done. With just two groups reporting here, only a limited assessment of the overall effect of the ADH cluster and the GABA cluster is possible. However, these loci have merit as candidate genes, and thus further work on the current and additional families is clearly indicated.
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PMID:Chromosome 4 workshop. 968 26

Amino acid (glutamatergic, GABAergic) neuron deficiency theories of schizophrenia offer plausible explanations of pathogenesis. However, reports of disease-related reductions in amino acid synthesizing enzymes in post-mortem brains are contradictory. We measured neuronal uptake sites for gamma-aminobutyric acid (GABA; [3H]nipecotic acid binding) and nerve terminal/glial uptake sites for L-glutamate (D-[3H aspartate binding) in three independent groups of post-mortem brains from patients with schizophrenia and control subjects. Measurements were also made of the phencyclidine site of the glutamate N-methyl-D-aspartate (NMDA) receptor. Samples from patients showed no reductions in the binding of [3H]nipecotic acid or D-[3H]aspartate in caudate, putamen or globus pallidus. On the contrary, some increased binding of both ligands was observed in patients in many comparisons with controls. There were no clear-cut changes in NMDA receptor binding. The most consistent change in the brain sets was increased [3H]nipecotic acid binding in caudate-putamen. This could be due to neuroleptic treatment. The findings produce no evidence that schizophrenia involves major loss of GABA neuron terminals in the basal ganglia or losses of corticostriatal glutamatergic projections.
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PMID:Absence of basal ganglia amino acid neuron deficits in schizophrenia in three collections of brains. 968 21


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