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)

Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A neuroleptic-like effect of ceronapril on latent inhibition. 135 53

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

Thirty years ago, dopamine was identified as an essential neurotransmittor. Since then, it has been the most written about CNS molecule. Considerable evidence implicates disturbances of brain dopamine function in the pathophysiology of several psychiatric and neurologic disorders, especially schizophrenia and Parkinson's disease. In the last decade, there have been important advances in the understanding of the diversity of CNS dopamine neurons and the chemical basis of this diversity, which relies upon molecular physiology of D1 and D2 receptors. Heterogeneity is remarkable at different levels, anatomical, biochemical, morphological or functional; besides, region specific interactions with other neurotransmittors and sometimes colocalisation of dopamine with cholecystokinin and/or neurotensin suggest the integration of dopamine neurons in functional subunits.
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PMID:[The mesencephalic dopaminergic system. Implications for neuroleptic treatment]. 197 42

The ventral mesencephalons of hamster, guinea pig, cat, monkey, and several humans with and without the diagnosis of schizophrenia were analyzed with in situ hybridization and immunohistochemistry. Extensive codistribution of cholecystokinin mRNA and tyrosine hydroxylase [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] mRNA was observed in cats and monkeys as well as in all five human subjects with the diagnosis of schizophrenia and in two out of five control brains. Double labeling revealed coexistence of the two markers in cat, monkey, and human. No cholecystokinin mRNA or cholecystokinin peptide was detected in the substantia nigra/ventral tegmental area of the hamster or guinea pig, even after acute and chronic neuroleptic treatment.
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PMID:Analysis of expression of cholecystokinin in dopamine cells in the ventral mesencephalon of several species and in humans with schizophrenia. 197 24

Recently much interest has been shown in the antipsychotic efficacy of neuroleptic-like neuropeptides in schizophrenia. In this article the clinical effects of the non-opioid fragments of gamma-endorphin, the so-called gamma-type endorphins DT gamma E and DE gamma E are reviewed. In addition, preliminary clinical studies of peptides related to cholecystokinin are considered. It is concluded that gamma-type endorphins possess antipsychotic properties in a subgroup of patients who may belong to Type I schizophrenia. With cholecystokinin-related peptides, in particular ceruletide, antipsychotic effects have been reported, which seem to be more or less comparable to those observed with gamma-type endorphins.
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PMID:[Antipsychotic efficacy of neuroleptic neuropeptides in schizophrenia. Review of clinical data]. 245 39

Evidence has accumulated to implicate neuropeptides localized within midbrain dopamine neurons (cholecystokinin, neurotensin, acetylcholinesterase) in synaptic transmission, mental disease, and pharmacotherapy. We suggest a means by which antipsychotic drugs alter the dynamics between dopamine and colocalized peptides: the intrinsic ability of these agents to stimulate dopamine neuronal activity while blocking dopamine receptors modulates the ratio of catecholaminergic to peptidergic transmission within the mesotelencephalic system. Imbalances of peptide and dopamine cotransmission and their modulation by neuroleptics may be relevant to the pathogenesis and pharmacotherapy of schizophrenia.
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PMID:A mechanism for the involvement of colocalized neuropeptides in the actions of antipsychotic drugs. 256 35

Ceruletide, an analog of cholecystokinin (CCK), has been reported to have neuroleptic-like activity in mice, and, in three open studies, to benefit schizophrenic patients. This study evaluated ceruletide in schizophrenia using a double-blind design. Subjects were 17 chronic schizophrenics with residual symptoms following stabilization with neuroleptics. Patients randomly received two injections, 1 week apart, of either ceruletide (0.6 microgram/kg im) or placebo, while continuing neuroleptics; this regimen was found helpful in earlier studies. Evaluation included ratings of 29 variables related to prognosis in schizophrenia (e.g., age, number of previous hospitalizations), regular BPRSs and SCL-90s, and psychiatrist, patient, and relative ratings of global improvement. Results showed few significant differences between ceruletide and placebo, with exceptions as likely to favor placebo as ceruletide. Among the patients on ceruletide, no predictors of benefit were found. Possible reasons for the negative results are discussed.
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PMID:Ceruletide for schizophrenia: a double-blind study. 285 54

The long-term administration of neuroleptics causes tardive dyskinesia, which closely resembles levodopa-induced dyskinesias, and is brought about through complex mechanisms which are ill-defined. It is generally believed that the pathogenesis of tardive dyskinesia relates closely to the chronic blockade of dopamine receptor sites and that its pathophysiology results from a hypersensitivity of dopamine receptor sites. In the therapeutic management of neuroleptic-induced tardive dyskinesia, in addition to reserpine and lithium, diazepam, baclofen, or gamma-vinyl-gamma-aminobutyric acid have also been advocated. However, the reported beneficial effects of diazepam and GABA-mimetic agents in ameliorating the symptoms of tardive dyskinesia may occur through a mechanism which does not necessarily link transmission involving both dopamine and GABA. The presence of high concentrations of both cholecystokinin and opioids in the striatum also suggests that these peptides not only may influence dopaminergic transmission, but that they may also be relevant to the psychopathology of schizophrenia and to the therapeutic effects of neuroleptics. Indeed, the acute and chronic administration of neuroleptics alters the levels of cholecystokinin and opioids and their receptors in several brain regions including the striatum. However, neuroleptics also alter the biochemical integrity of neurotensin, neuropeptide Y, substance P and somatostatin, which may also play a role in the overall expression of the neuroleptic-induced extrapyramidal reactions.
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PMID:Dopamine, GABA, cholecystokinin and opioids in neuroleptic-induced tardive dyskinesia. 290 20

Neurons in the hippocampal formation of the rat that project to the medial nucleus accumbens were identified following the retrograde transport of a conjugate of horseradish peroxidase with wheat germ agglutinin. The great majority of such projecting neurons were located in the ventral subiculum and were pyramidal in shape; the pyramidal nature of 25 such retrogradely labelled neurons was established by Golgi impregnation. In material processed to reveal both retrogradely labelled cells and cholecystokinin-immunoreactivity, no immunoreactive projecting neurons were found. However, 48 identified projecting neurons, probably pyramidal, were found to receive input from cholecystokinin-immunoreactive boutons that formed symmetrical synaptic contacts with the soma or proximal dendrites. It is suggested that one function of cholecystokinin-immunoreactive neurons in the hippocampal formation might be to influence the output of the pyramidal neurons that project to the nucleus accumbens. Since this pathway is one of the main links between the limbic system and the basal ganglia, it is conceivable that changes in the cholecystokinin levels in the hippocampus, as found in schizophrenia, might influence behaviour through the pathway connecting the hippocampus with the nucleus accumbens.
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PMID:Cholecystokinin-immunoreactive boutons in synaptic contact with hippocampal pyramidal neurons that project to the nucleus accumbens. 302 63

Cholecystokinin (CCK) is a peptide originally isolated from the gut. It has been investigated as a candidate treatment for schizophrenia on the assumption that the illness is associated with an imbalance between CCK and dopamine in the mesolimbic dopamine system. Many of the studies to assess the efficacy of CCK used open designs and are prone to observer bias and over-optimistic reporting. Most of the studies used CCK as an adjunct to standard neuroleptic treatment and are too small to be able to demonstrate extra efficacy above that of the active compound. Only three out of ten studies using CCK or placebo as an adjunct to neuroleptics reported limited efficacy. Of the 14 placebo-controlled reports only three were in drug-free patients. These were unfortunately too small, or too brief, to draw valid conclusions of efficacy. A summary of these data suggests that although 500 patients have received CCK, its efficacy in the treatment of schizophrenia has not been properly tested.
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PMID:The use of cholecystokinin in schizophrenia: a review. 305 90


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