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)

Neuropathological, neuroimaging, clinical and epidemiological evidence suggests that many cases of schizophrenia are developmental in origin. Dysplastic changes in the medial temporal lobes appear to be of particular importance. However, research implicating a neurodevelopmental origin for schizophrenia has proceeded largely in isolation from knowledge concerning the neurochemistry of the disorder. This paper attempts to integrate these disparate lines of research, and examines the role of trophic mechanisms in the formation of the hippocampus. Those neurotransmitters which have been most consistently found to be abnormal in the temporal lobes of schizophrenics (excitatory amino acids and CCK), are involved in the control of hippocampal development. We suggest that these neurotransmitter findings are the residue of abnormalities in their role as trophic factors in foetal or neonatal life, and that the latter contribute to the developmental aberrations considered fundamental to schizophrenia.
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PMID:A developmental perspective on the pathology and neurochemistry of the temporal lobe in schizophrenia. 135 Apr 59

The distribution of cholecystokinin binding sites has been visualized and quantified by quantitative autoradiography in the human hippocampus from post-mortem brains of 11 controls and 11 schizophrenics. CCK receptors were localized to subiculum and parahippocampal gyrus. In the cortical areas there was a particularly dense lamination of receptors. In the schizophrenic material a similar overall pattern was seen, but there were significant losses of receptors in CA1 subiculum and cortex. These findings confirm the distribution of CCK receptors in the retrohippocampal areas in man and also provide further support for earlier homogenate studies which have also shown a loss of CCK binding sites in schizophrenia. This effect was localized primarily to parahippocampal gyrus suggesting that CCK plays some role in the genesis of developmental abnormalities in this region.
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PMID:Distribution of CCK binding sites in the human hippocampal formation and their alteration in schizophrenia: a post-mortem autoradiographic study. 157 65

Using the in vitro quantitative receptor autoradiographical technique, changes in the binding parameters of [propionyl-3H] propionylated CCK-8 [( 3H]pCCK-8) binding sites in the rat forebrain were investigated following acute and chronic administration of methamphetamine (MAP). The (Kd)app values of [3H]pCCK-8 binding sites in the frontal medial cortex and anterior cingulate cortex were significantly reduced after a single injection of 4mg/kg MAP. On the other hand, chronic treatment (14 days) with MAP at this dose significantly decreased the Bmax value of [3H]pCCK-8 binding sites in the anterior cingulate cortex accompanied by supersensitivity of locomotor effects to MAP. These findings suggest that dopamine (DA) neurons in these two regions are functionally related to intrinsic CCK-containing cortical neurons, and that CCK subsensitivity, perhaps due to an alteration in DA transmission, is involved in MAP sensitization. These findings may be relevant to the DA hypothesis of schizophrenia.
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PMID:Cholecystokinin binding sites in the rat forebrain: effects of acute and chronic methamphetamine administration. 276 Jun 4

CCK-IR is co-localized with DA in some DA neurons projecting to limbic structures. The extent of the co-localization is species dependent. The co-localization of CCK and DA is of interest in view of the DA hypothesis of schizophrenia and the putative role of limbic dysfunction in the pathophysiology of this disorder. In animals biochemical, electrophysiological and behavioural studies point to an interaction between CCK and DA. Whereas some investigations point to an inhibitory effect on DA function, which would be compatible with a potential antischizophrenic action, others point to an enhancement or no effect. CCK peptides show a neuroleptic-like profile in several screening tests for neuroleptics but not in all studies. In man there is endocrinological evidence for an inhibitory effect of CCK-33 and CCK-8 on DA function. However, alternate explanations are possible. CSF CCK-IR is unchanged or decreased in schizophrenia. Autopsy investigations have shown significant decreases, increases or no change in brain CCK-IR concentrations and a decrease in CCK-33 binding in schizophrenia. Eight of 11 clinical trials with CER, CCK-8 or CCK-33 have shown a therapeutic effect in schizophrenia; only two of these eight trials have been double-blind studies. The three controlled investigations which have shown no effect have used only small patient populations. None of the trials have used an active placebo. It is difficult to reconcile the apparent long duration of antipsychotic activity with the short half-life of the peptides and problems of the peptides in crossing the blood brain barrier. Despite these apparent anomalies information to date is sufficiently impressive to warrant further detailed investigation of CCK-DA-interactions and the evaluation of the clinical effects of a variety of CCK peptides and related compounds, natural and synthetic, which may more easily cross the blood brain barrier and which may show regional selectivity in site of action in brain.
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PMID:Cholecystokinin peptides, dopamine and schizophrenia--a review. 286 91

1. CCK-peptides are distributed throughout the whole brain with the exception of the cerebellum. 2. There is strong evidence that they act as neuromodulators on the noradrenergic, opioid and mainly dopaminergic system. 3. CCK reduces food-intake. However, tolerance occurs, when chronically given. Thus, potential benefits in the treatment of obesity seem unlikely. 4. CCK increases threshold and tolerance to electrically and thermally induced cutaneous pain. CCK yields relief of pain in colic and ischaemic pain. 5. To date, results about CCK-content in CSF and post-mortem-brain in various psychiatric and neurological diseases related to the dopaminergic system are equivocal. 6. Treatment studies do not provide evidence for beneficial effects of CCK-peptides in schizophrenia.
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PMID:Cholecystokinin. 307 40

Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide, a cholecystokinin-like peptide, in a placebo-controlled, double-blind, crossover study. Ceruletide or placebo was administered intramuscularly twice a day for 4 consecutive days while patients were maintained on a constant dose of fluphenazine. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo and ceruletide administration. To further characterize ceruletide actions we also administered it to seven normal volunteers and evaluated its effects on cognition and mood. Volunteers were administered ceruletide (0.3 micrograms/kg or 0.6 micrograms/kg) or saline placebo intramuscularly. Ceruletide had no effects on recent or remote memory or attention, but the higher dose did cause a significant increase in fatigue. These results suggest that although CCK-like peptides lack antipsychotic or cognitive effects they do induce mild sedation. This sedation may be part of a "satiety-like" state induced by peripheral administration of CCK.
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PMID:The effects of cholecystokinin-like peptides in schizophrenics and normal human subjects. 389 99

Antipsychotic properties of cholecystokinin have been suggested both in laboratory studies and in some open clinical trials, mainly in patients suffering from chronic schizophrenia. Eighteen patients (14 males, 4 females) meeting Research Diagnostic Criteria for schizophrenia had been receiving neuroleptics at a dosage that had not changed for 3 months, and to which the patients were at best only partially responsive. The patients were randomized into groups that received weekly intravenous injections of 10 micrograms of CCK-8 or normal saline over 8 weeks. Neuroleptic medication was unchanged for the study. Baseline and weekly assessments were carried out using the Brief Psychiatric Rating Scale (BPRS) and the Schizophrenia Subscale of the Present State Examination (SS-PSE). Analysis of covariance revealed significant differences between CCK-8 and placebo over the study period on the Thought Disturbance Factor and Total Score of the BPRS, and on the Nuclear Syndrome, Total Delusion Factor, and Total Score of the SS-PSE. No important side effects were noted. It is concluded that CCK-8 has definite antipsychotic properties in patients with chronic schizophrenia. Clinical trials in neuroleptic-free patients are warranted.
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PMID:Cholecystokinin-octapeptide in chronic schizophrenia: a double-blind placebo-controlled study. 615 44

Caerulein, a decapeptide chemically related to CCK-8, was administered intramuscularly to 20 patients with chronic schizophrenia in two different doses of 0.3 and 0.6 microgram/kg. BPRS ratings were made before and 3 weeks after the injection. The neuroleptic therapy was not discontinued, but both drug and dose were not changed at least 3 weeks before the first injection and during the study period. Clinically obvious and statistically significant improvement in psychotic symptoms occurred shortly after the injection of caerulein. The greatest change occurred 1--2 weeks later. There was an evident correlation between the observed changes and the dose injected. Our findings suggest that caerulein has a long-acting, antipsychotic activity in chronic schizophrenia. Furthermore, our findings suggest the involvement of CCK-like peptides in the pathogenesis of schizophrenia.
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PMID:Antipsychotic effects of caerulein, a decapeptide chemically related to cholecystokinin octapeptide, on schizophrenia. 718 70

Receptor diversity in combination with receptor-receptor subtype specific interactions, which can be antagonistic or synergistic in character, markedly increase plasticity in WT and VT in the nervous system. In this way switching among transmission lines for the various DA receptor subtypes becomes possible. Some of these aspects are supported by our work on selective modulation of D2 receptors by CCK and NT. Selective regulation of D2 receptors via CCK-8 receptor subtypes and NT receptors may underlie CCK/DA interactions and NT/DA interactions in the basal ganglia. These studies underline the importance of receptor-receptor interactions exerted at the membrane level between neuropeptide receptors and D2 receptors, which are determined at least in part by the ongoing activity at D1 receptors. In the case of both CCK/D2 and NT/D2 receptor interactions, it has been possible, by means of intrastriatal and intraaccumbens microdialysis, to obtain a functional correlate to the receptor interactions found in the membrane preparations from the striatum. Schizophrenia may be in part related to reduced release of CCK and/or NT peptides or to alterations in their receptor interactions with the D2 receptor. This view may lead to new therapeutic approaches.
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PMID:Receptor-receptor interactions and their relevance for receptor diversity. Focus on neuropeptide/dopamine interactions. 761 94

The effects of chronic methamphetamine (MAP) administration (at a dose of 4 mg/kg for 14 days) on [3H]pCCK-8 binding sites in the rat brain were investigated by an in vitro quantitative receptor autoradiographic technique. The number of [3H]pCCK-8 binding sites was significantly reduced in layers III and IV of the medial frontal, anterior, and posterior cingulate cortices, in layers II-IV of the retrosplenial cortex, in layers III-VI of the dorsal insular cortex, and in the reticular nucleus of the thalamus, compared to these numbers in a control group of rats that received physiologic saline. Further, chronic methamphetamine administration led to a significant increase in the number of these binding sites in layer I of the entorhinal cortex. These findings indicate the CCK peptides in the limbic lobe may be closely related to the development of the behavioral changes associated with methamphetamine sensitization. In addition, these results provide supporting evidence for the involvement of the limbic system in the pathophysiology of schizophrenia.
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PMID:Autoradiographic localization of CCK-8 binding sites in the rat brain: effects of chronic methamphetamine administration on these sites. 829 82


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