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)

In this study, a PstI polymorphic site with two individual alleles, namely A1 and A2, was identified withinthe boundary between intron 1 and exon 2 of the cholecystokinin (CCK) type A receptor gene. The PstI polymorphic site was used as a genetic marker to study its association with psychotic symptoms in schizophrenia. A significant difference in allelic frequency was found between schizophrenic patients with and without auditory hallucinations(chi(2) = 6.26, df = 1, P = 0.012), and the odds ratio for the allelic association was 2.21 (95% CI 1.18-4.15) with an attributable fraction of 0.1. The frequency of A1-A1 and A1-A2 genotypes showed a significant excess in schizophrenic patients with auditory hallucinations as compared to those without such symptoms (chi(2) = 5.45, df = 1, P = 0.02), and the odds ratio for the genotypic association was 2.27 (95% CI 1. 13-4.57) with an attributable fraction of 0.177. The haplotype-based haplotype relative risk (HHRR) test revealed a significant difference between transmitted and non-transmitted alleles in nuclear families of schizophrenic patients with auditory hallucinations (chi(2) = 4.54, df = 1,P = 0.033) but not in those of schizophrenic patients without them. The present study suggests that the CCK-A receptor gene may be associated with auditory hallucinations in schizophrenia.
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PMID:The CCK-A receptor gene possibly associated with auditory hallucinations in schizophrenia. 1057 28

In the light of earlier findings of reduced cholecystokinin (CCK) peptide and CCK mRNA levels in the cerebral cortex, we have used in situ hybridization to examine possible regulation of mRNAs coding for two isoforms of the CCK(B) receptor in frontal cortex (Brodmann's area 10) of schizophrenic patients. The hybridizations revealed a 51% decrease of the full length CCK(B) receptor mRNA in the outer layers (II-III) of the frontal cortex. The corresponding alterations for the truncated isoform were a 65% reduction in the outer layers and a 62% reduction in the inner layers (IV-VI) of the frontal cortex. This strengthens the hypothesis that CCKergic transmission in this part of the brain is involved in the pathophysiology of schizophrenia.
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PMID:Cholecystokinin CCK(B) receptor mRNA isoforms: expression in schizophrenic brains. 1059 31

The antipsychotic potential of cholecystokinin (CCK)-related compounds stems from CCK's colocalization with dopamine (DA). CCK demonstrates excitatory and inhibitory effects on DA in the mesolimbic pathway. Such diverse actions might be mediated by different receptor subtypes (CCK(A) or CCK(B)). Multiple hypotheses have emerged regarding the clinical application of CCK-based drugs. Administering selective nonpeptide antagonists within animal models relevant to schizophrenia would help delineate CCK receptor involvement. One animal model simulating a cognitive dysfunction of schizophrenia is latent inhibition (LI). An animal repeatedly exposed to a stimulus that is devoid of consequence is subsequently inhibited in making new associations with that stimulus. This reflects a process of learning to ignore irrelevant stimuli. The present study examined the effects of the selective CCK(B) antagonist PD-135,158 (0.001, 0. 01, and 0.1 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. PD-135,158 (0.1 mg/kg), similar to haloperidol (0.1 mg/kg), elicited a clear LI effect under conditions that did not lead to LI in control rats (low number of preexposures). These findings highlight the antipsychotic potential of CCK(B) antagonists, and further illustrate the LI paradigm's capacity to detect novel, antipsychotic-like, drug activity.
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PMID:PD-135,158, a cholecystokinin(B) antagonist, enhances latent inhibition in the rat. 1068 86

Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Sp1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation.
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PMID:Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter. 1088 57

This paper is a review of a recent findings on the pathology of hippocampal interneurons in schizophrenia, with specific emphasis on a protein expressed by these cells, the alpha7-nicotinic acetylcholine receptor subunit. Convergent information indicates that interneurons in the hippocampus and other forebrain structures are decreased in number and function in subjects with schizophrenia. Among the neurochemical markers that are decreased in the hippocampus are synapsin I, cholecystokinin, somatostatin, glutamic acid decarboxylase, and nitric oxide synthase. GABA uptake sites and the GABA synthetic enzyme glutamic acid decarboxylase are also diminished. Included among these findings is decreased binding of alpha-bungarotoxin, which binds to low-affinity nicotinic acetylcholine receptors, such as the alpha7-nicotinic receptor. Co-labeling experiments in rodents indicate that these markers are expressed on overlapping populations of hippocampal interneurons. Thus, the finding of decreased neurochemical function of hippocampal interneurons is a widely replicated finding, with different groups reporting markedly similar findings using independent post mortem samples and different neurochemical strategies. Decreased alpha-bungarotoxin binding or decreased alpha7-nicotinic receptor immunoreactivity has also been found in the frontal cortex and in the nucleus reticularis thalami of schizophrenic subjects. The alpha7-nicotinic receptor subunit gene on chromosome 15q14 is a site of heritability for schizophrenia and bipolar affective disorder, and in, particular, for a deficit in inhibitory neuronal function associated with these illnesses. Thus, the post mortem data are further supported by psychophysiologic and genetic investigations that indicate a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor. The alpha7-receptor is a ligand-gated ion channel that admits calcium ions into cells, and it has been proposed to have various developmental roles. Its malfunction may be part of the developmental pathogenesis of schizophrenia.
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PMID:The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. 1120 27

The cholecystokinin gene (CCK) is thought to play a role in the pathogenesis of both panic disorder and schizophrenia. In this study, we have extended the 5'-upstream sequence of the CCK gene, and identified a compound short tandem repeat (STR), located approximately -2.2 to -1.8 kb from the cap site. This STR was found to be polymorphic with ten different allele lengths. Case-control studies using 73 panic patients, 305 schizophrenics and 252 controls showed a significant allelic association with panic disorder (P = 0.025), but not with schizophrenia. Dividing the STR alleles into three classes according to length, Long (L), Medium (M) and Short (S), produced strong genotypic (MM) (nominal P = 0.0014) and allelic (M) (nominal P = 0.0079) associations with panic disorder. screening the newly extended promoter region detected not only the previously identified -36c>t and -188a>g single nucleotide polymorphisms (SNPs) but a new rare snp, -345g>C. Neither of the former two SNPs showed significant association with either panic disorder or schizophrenia. Haplotypic distributions of the STR and SNPs -188 and -36 were significantly different between panic samples and controls (P = 0.0003). These findings suggest that the novel STR or a nearby variant may confer susceptibility to the development of panic disorder.
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PMID:Identification of a compound short tandem repeat stretch in the 5'-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia. 1144 35

Cholecystokinin A receptors (CCKAR) modulate CCK-stimulated dopamine release, and mutations in the CCKAR gene may predispose affected individuals to schizophrenia. Our previous study suggested that -286A>G polymorphism (previously named 201A>G) in the CCKAR gene promoter is associated with schizophrenia. In the present study, we carried out a further investigation of the promoter and intron 1 of the CCKAR gene. In addition to polymorphisms reported previously (-333G>T, -286A>G, -241G>A, 773A>T, and 779T>C), two novel polymorphisms (-388(GT)(8)>(GT)(9) and -85C>G) were identified. These polymorphisms were in a linkage disequilibrium. Association analyses between schizophrenic patients and controls revealed that the frequencies of the A allele and AA genotype at the -286 loci, as well as the frequency of the GG genotype at the -333 loci, were significantly higher in patients than in controls. Furthermore, patients with paranoid type schizophrenia, auditory hallucinations, or a positive family history had a significantly higher frequency of the -286A allele than the control group. The results supported our previous data, and suggest the possible involvement of the -333G>T and the -286A>G polymorphisms in the promoter region of the CCKAR gene in the predisposition to schizophrenia.
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PMID:Linked polymorphisms (-333G>T and -286A>G) in the promoter region of the CCK-A receptor gene may be associated with schizophrenia. 1154 3

The tetrapeptide of cholecystokinin (CCK), CCK-4, is known to induce panic attacks in human subjects, while CCK-8 is reported to have a therapeutic effect on schizophrenia symptoms. Recently, we have identified a novel microsatellite polymorphism in the 5' upstream region of the CCK gene and shown a significant association between this polymorphism and panic disorder. In this study, we have investigated the CCK-B receptor (CCKBR) gene, which is the main constituent of the CCK receptor in the CNS. Recently, a dinucleotide repeat, (CT)(n), in the 5' regulatory region of the CCKBR gene was reported to be associated with panic disorder in Canadian samples. To evaluate an association of the CT repeat with panic disorder and schizophrenia, we genotyped 71 subjects with panic disorder, 154 schizophrenics and 199 controls. However, no evidence of allelic association was found between the polymorphic repeat of the CCKBR gene and either panic disorder or schizophrenia (P = 0.186 and 0.987, respectively). Together with the negative reports on association analyses using other polymorphisms of the CCKBR gene and Japanese samples, the present results exclude a major genetic contribution of the CCKBR gene to susceptibilities to panic disorder and schizophrenia in Japanese cohorts.
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PMID:Association studies of the CT repeat polymorphism in the 5' upstream region of the cholecystokinin B receptor gene with panic disorder and schizophrenia in Japanese subjects. 1180 30

Latent inhibition (LI) is a behavioural paradigm in which repeated exposure to a stimulus without consequence inhibits the formation of any new associations with that stimulus. To the extent that LI reflects a process of leaming to ignore irrelevant stimuli, disrupted LI has been suggested as an animal model for the attentional deficits observed in schizophrenia. The antipsychotic potential of cholecystokinin (CCK) stems from its colocalization with dopamine (DA) in the mesolimbic pathway, where it demonstrates both excitatory and inhibitory effects on dopaminergic activity. This may be explained by mediation through different receptor subtypes. A variety of hypotheses has emerged regarding the potential clinical application of subtype-selective CCK-based drugs. The present experiments examined the effects on LI of two selective CCK(A) ligands: PD-140,548 (a CCK(A) antagonist, Experiment 1: 0.001, 0.01, and 0.1 mg/kg) and A-71623 (a CCK(A) agonist, Experiment 2: 0.02, 0.05, and 0.1 mg/kg). In both experiments, the effects of haloperidol (0.1 mg/kg) were also investigated. Animals receiving 0.1 mg/kg of haloperidol or 0.001 or 0.1 mg/kg (but not 0.01 mg/kg) of PD-140,548 treated the preexposed stimulus as irrelevant after a low number of preexposures. In contrast, no facilitatory effect on LI was detectable at any of the A-71623 doses. The finding that A-71623 failed to enhance LI indicates that it is unlikely that this compound would have any antipsychotic effect within the clinical setting. Considering the facilitatory effect exerted by PD-140,548 on LI, it is probable that the inhibition of CCK activity might prove a more promising strategy for the pharmacological treatment of schizophrenia.
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PMID:Differential effects of the CCKA receptor ligands PD-140,548 and A-71623 on latent inhibition in the rat. 1199

Several lines of research indicate a cholecystokinin (CCK) deficit in schizophrenia patients. A C to T substitution was found in the promoter region of the CCK gene. We investigated this promoter variant in patients with schizophrenia and geographically-matchedcontrols. The T allele was detected in 24% of the 85 schizophrenics and 16% of the 247 controls. No significant difference in the T allele frequency was found between patients and controls (chi(2) = 2.77, P > 0.1). The schizophrenia sample was analyzed further along the dimensions of positive and negative symptoms. The patients with prominent negative symptoms presented a statistically significant association to the T allele (chi(2) = 4.13, P < 0.04). However, the significance disappeared after the Bonferroni correction (P > 0.15). Since the case-control analysis may present incorrect ethnic match between cases and controls, we applied the family-based tests to verify the above findings. Both transmission disequilibrium test (TDT; chi(2) = 5.33, P < 0.025 in 12 trios) and haplotype relative risk (HRR; chi(2) = 3.844, P < 0.05 in 60 trios) indicated a significantly high transmission of T allele to schizophrenia offspring probands from their parents. While our family-based tests seem to support the CCK involvement in schizophrenia, no definite conclusion can be drawn based on such a small sample size. This preliminary finding is subjected to future investigations.
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PMID:Possible association of a cholecystokinin promoter variant to schizophrenia. 1211 80


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