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)

Alteration in dopamine (DA) and/or cholecystokinin (CCK) transmission in the CNS may be of relevance for schizophrenia. Previous findings in striatal membranes give indications of a modulation of DA D2 receptor affinity by CCKB receptor activation. In the present study receptor binding studies were performed in a mouse fibroblast cell line (L-hD2l/CCK), expressing both human D2 receptors (long form, D2L) and human CCKB receptors, and binding sites for [3H]CCK-8S (sulfated CCK octapeptide), the D2 agonist [3H]NPA and the D2 antagonist [3H]raclopride were found and characterized in saturation and competition experiments. 1 nM of CCK-8 caused a significant 38% increase in the KD value of the D2 agonist [3H]NPA binding sites in the L-hD2l/CCK cell membranes. This change was blocked by the CCKB receptor antagonist PD 134308 (50 nM). Furthermore, 1 nM of CCK-8 increased the KD value of the D2 antagonist [3H]raclopride binding sites by 34% (P < 0.05) in the L-hD2l/CCK cell membranes. Control cells (L-hD2l cells) expressing D2L receptors showed no specific [3H]CCK-8S binding sites and no modulation by CCK-8 of the D2L receptors. These findings indicate a modulation of the D2L receptor affinity by activation of the CCKB receptor also when they are coexpressed in a fibroblast cell line. One possible explanation of these data may include a receptor-receptor interaction between the CCKB and D2L receptors.
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PMID:Regulation of dopamine D2 receptor affinity by cholecystokinin octapeptide in fibroblast cells cotransfected with human CCKB and D2L receptor cDNAs. 896 50

In this article, recent information from neuropathological studies in humans and behavioural and electrophysiological/pharmacological studies in rats is used to examine the hypothesis that the subiculum, the major output region of the hippocampal formation, may contain sites of action for novel antipsychotic drugs. In the first section, the possible interactions between subicular neurons and the sites at which existing antipsychotic drugs act are discussed. These include the interaction implied by convergence of subicular and dopaminergic inputs to the nucleus accumbens. The second section concentrates upon subicular involvement in animal behaviours that are thought to be relevant to schizophrenia, which, in rats, include Latent inhibition and Pre-pulse inhibition of Acoustic Startle. Involvement of the subiculum in the neuropathology of schizophrenia is discussed in the third section. However, few neuropathological studies comment specifically on the subiculum. Those which suggest involvement tend to be recent and, as yet, have not all been replicated. Finally, there is discussion of the possibility that the subiculum contains chemical sites at which drugs could act specifically to produce appropriate physiological effects. Potential sites include, but are not necessarily restricted to, particular ion channels in electrophysiologically defined subclasses of subicular pyramidal neurons, the receptors for neuromodulatory peptides such as somatostatin and cholecystokinin, and the enzyme nitric oxide synthase. It is concluded that a wide range of clinical and basic neuroscience disciplines has provided evidence which, especially when viewed as a whole, is consistent with the hypothesis that the subiculum is a potential site of action for novel antipsychotic drugs.
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PMID:The subiculum: a potential site of action for novel antipsychotic drugs? 915 31

The effects of cholecystokinin (CCK) in an animal model of sensorimotor-gating deficits with strong face, construct and predictive validity for schizophrenia were investigated. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus inhibits the startle response to a loud startling stimulus. Infusions of sulfated CCK-8 in the posterior nucleus accumbens potentiated apomorphine-induced disruption of PPI but had no effect on baseline PPI or the amplitude of acoustic startle reflex itself. The results provide evidence that mesolimbic CCK may play a role in regulating sensorimotor gating deficits but contradict earlier notions that CCK agonists may have antipsychotic properties and upon which clinical trials of CCK agonists in schizophrenia were based. Rather, these results suggest that antagonists of CCK may display neuroleptic-like actions on deficits in PPI and may hold greater promise as antipsychotics.
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PMID:The modulation of sensorimotor gating deficits by mesolimbic cholecystokinin. 922 88

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

The evidence for a significant genetic contribution to the functional psychoses (schizophrenia and bipolar disorder) is now well established. However, in both cases, the non-mendelian mode of inheritance has made the identification of susceptibility loci particularly challenging. The neuropeptide cholecystokinin (CCK) is present both in the gut and the CNS. Studies of CCK-like immunoreactivity and CCK mRNA levels in human brains have revealed high concentrations in numerous loci and shown colocalisation of CCK with, for example, dopamine and tyrosine hydroxylase. Furthermore, antagonists of CCK-B receptors, which are found most frequently in the brain, inhibit the activity of brain dopamine neurons. Such findings suggest that, with respect to neuropsychiatric disorders, CCK is a suitable candidate for analysis using methods to detect gene variations which have the potential to affect protein structure or expression. In the present study, mutation analyses were carried out on the human CCK gene. Linked polymorphisms were found in the promoter region and in intron 1 close to the 3' mRNA splice acceptor site. However, the allele frequencies of these polymorphisms in samples of individuals affected with either schizophrenia (n=117) or bipolar disorder (n=124) did not differ from those of control subjects (n=234), suggesting that these variations do not confer a predisposition to either of the functional psychoses.
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PMID:Linked polymorphisms upstream of exons 1 and 2 of the human cholecystokinin gene are not associated with schizophrenia or bipolar disorder. 949 15

The behavioral paradigm of latent inhibition (LI) involves the retardation of conditioning to a stimulus when paired with reinforcement, if preexposure to that stimulus with no significant consequence has occurred. This phenomenon is believed to reflect a process of learning to ignore stimuli as irrelevant. Disruption in LI can be considered to be an attentional deficit observed in schizophrenia. The neuropeptide cholecystokinin (CCK), which coexists with dopamine (DA) in some brain regions, has been implicated in the pathophysiology of schizophrenia. The present study examined the effects of the nonselective CCK antagonist proglumide on LI (0.25, 0.5, and 1.0 mg/kg) using a conditioned suppression of drinking procedure in rats. For purposes of comparison the effects of haloperidol (0.1 mg/kg) were also investigated. Administration of 1.0 and 0.5 mg/kg, but not 0.25 mg/kg, proglumide was found to reduce suppression of drinking behavior in animals preexposed (PE) to a flashing light stimulus. These animals developed LI under conditions where preexposed control animals exhibited suppression of drinking behavior similar to that of nonpreexposed (NPE) control animals. These findings for proglumide were comparable to the effects on drinking behavior of 0.1 mg/kg haloperidol. The enhancement of LI by proglumide may be interpreted in terms of CCK dopamine interactions. Because CCK may modulate dopamine, the results reported here for proglumide strengthen the argument for the investigation of CCK-based drugs as potential antipsychotic agents.
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PMID:Enhancement of latent inhibition in the rat by the CCK antagonist proglumide. 958 67

Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to modulate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments.
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PMID:Antipsychotic potential of CCK-based treatments: an assessment using the prepulse inhibition model of psychosis. 988 94

The hippocampal formation (HF) has been a centerpiece of neuropathologic investigations of schizophrenia. Numerous MRI studies have demonstrated a slight bilateral reduction in HF volume. Reports of reduced N-acetyl aspartate measured with in vivo proton spectroscopy suggest that neuronal pathology exists. However, morphometric data from postmortem studies have not revealed a clear change in HF size, and recent studies of neuronal number and of cytoarchitecture have been largely negative. Evidence of glial proliferation is consistently absent. The most reproducible positive anatomic finding in postmortem HF has been reduced size of neuronal cell bodies. Studies of gene transcription have provided replicable evidence of decreased expression of mRNAs for synaptophysin, GAP-43, cholecystokinin, and non-NMDA glutamate receptor subunits (GLU R 1 and 2), particularly in CA 3-4. These data about the cellular and molecular biology of the HF in schizophrenia are different from that found in a number of conditions associated with hippocampal damage, including excitotoxicity, epilepsy, alcoholism, Alzheimer's disease, steroid neurotoxicity, and normal aging. Notwithstanding the real possibility that the data are epiphenomena of chronic illness, the findings may implicate a unique cellular defect in schizophrenia--a genetic variation affecting the plasticity of HF circuitry and connectivity. Directions for further research are proposed.
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PMID:Cell biology of the hippocampal formation in schizophrenia. 1007 7

There is evidence for the role of the cholecystokinin (CCK) neurotransmitter system in the neurobiology of panic disorder (PD). The CCK receptor agonist, CCK-tetrapeptide (CCK-4) fulfills criteria for a panicogenic agent and there is evidence that PD might be associated with an abnormal function of the CCK system. For example, PD patients show an enhanced sensitivity to CCK-4, and exhibit lower CSF and lymphocyte CCK concentration as compared to healthy controls (reviewed by Bradwejn et al.). Also, untreated PD patients display an increased CCK-4-induced intracellular Ca2+ mobilization in T cells relative to treated PD, depression and schizophrenia. The CCK receptors have been classified into two subtypes: CCK-A and CCK-B. We report here a study of polymorphisms in the CCK pre-pro hormone gene (CCK), CCK-AR, and CCK-BR in DSM-IV panic patients (n = 99) vs controls matched for gender and ethnicity. The CCK polymorphism revealed no association with PD. We identified a new polymorphism for the CCK-A receptor gene, and tested it in our sample, with negative results. A single nucleotide polymorphism has been found in the coding region of the CCK-B receptor gene (CCK-BR) and D Collier (personal communication) identified a highly polymorphic dinucleotide (CT)n microsatellite in the 5' regulatory region. For the CCK-B receptor gene polymorphism, PD patients showed a significant association. Our genetic dissection of the CCK system thus far suggests that the CCK-B receptor gene variation may contribute to the neurobiology of panic disorder.
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PMID:Investigation of cholecystokinin system genes in panic disorder. 1039 21

A study on the biology of 'panic disorder,' which I have classified under the category of 'anxiety disorder,' made progress recently. In a genetic study, the hereditary of panic disorder was checked by a 'linkage and twins' study, and the anticipation of panic disorder was recognized as being the same as that which is also found in the psychiatric conditions known as schizophrenia and manic depression. A panic disorder patient regards the anxious sign of a model as ruinous, and this weakness in recognition has been duly noted. Therefore, I studied a patient showing a continuance state of 'hyper-sensitivity,' and compared this to a patient showing a 'sleep disorder.' Noradrenaline plays an important role in anxiety as suppression of the locus ceruleus (LN), the major NE-containing nucleus of the noradrenaline nervous system, brings on a calming effect. Yohimbine, however, which is an alpha 2 antagonist, is found to induce panic attacks. The fact that selective serotonin reuptake inhibitor (SSRI) suppresses panic attacks suggests that serotonin is connected with panic disorders. It is also thought that the 'raphe nucleus' is the site of origin of the serotonin nervous system, which participates in the control of anxiety. This suggests the participation of a gamma-aminobutyric acid (GABA) nervous system in which the administration of benzodiazepine at a high potency would be an effective agent against panic disorder. Cholecystokinin (CCK) is also suggested to have a connection with panic disorder as CCK-4 causes panic attacks. There has been no CCK antagonist found effective for an object- or time-oriented panic disorder at the present. It is thought that corticotropin-releasing factor (CRF) is released during a panic attack. The development of a new CRF receptor antagonist is needed. In addition to the studies on the neurotransmitters of the traditional type, such as noradrenaline, serotonin and GABA, studies on the neuropeptides, such as CCK and CRF have become important for future consideration. Understanding this, image studies such as MRI, SPECT, fMRI and PET have become highly desirable.
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PMID:[Neuropharmacological and genetic study of panic disorder]. 1049 83


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