cholecystokinin and Schizophrenia

Topics: Anxiety; Cholecystokinin; Humans; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Schizophrenia

Schizophrenia, a debilitating illness affecting 0.5-1% of the world's population, is characterized by positive, negative and cognitive symptoms. The latter are the best predictor of functional outcome, though largely untreated by current pharmacotherapy; thus a better understanding of the mechanisms underlying cognitive deficits in schizophrenia is crucial. Higher order cognitive processes, such as working memory, are associated with θ (4-7 Hz) and γ (30-80 Hz) oscillations in the prefrontal cortex (PFC), and subjects with schizophrenia exhibit working memory impairments and reduced cortical θ and γ band power. Cortical θ and γ oscillations are dependent on perisomatic inhibition of pyramidal neurons from basket cells expressing cholecystokinin (CCK(b) cells) and parvalbumin (PV(b) cells), respectively. Thus, alterations in basket cells may underlie the cortical oscillation deficits and working memory impairments in schizophrenia. Recent findings from postmortem studies suggest that schizophrenia is associated with multiple molecular alterations that regulate signalling from CCK(b) and PV(b) cells. These alterations include lower CCK and cannabinoid 1 receptor (CB1R) in CCK(b) cells, and lower glutamic acid decarboxylase 67 (GAD67) and increased μ opioid receptor (μOR) in PV(b) cells, as well as lower GABA(A) receptor α1 subunit in pyramidal neurons postsynaptic to PV(b) cells. These changes are thought to lead to increased and decreased strength, respectively, of CCK(b) and PV(b) cell-mediated inhibition of postsynaptic pyramidal cells. Therefore, a convergence of evidence suggests a substantial shift in the relative strengths of PFC pyramidal cell inhibition from CCK(b) and PV(b) cells that may underlie cortical oscillation deficits and working memory impairments in schizophrenia.

Topics: Animals; Cholecystokinin; Humans; Interneurons; Parvalbumins; Pyramidal Cells; Schizophrenia

Gamma oscillations appear to be dependent on inhibitory neurotransmission from parvalbumin (PV)-containing gamma-amino butyric acid neurons. Thus, the abnormalities in PV neurons found in schizophrenia may underlie the deficits of gamma-band synchrony in the illness. Because gamma-band synchrony is thought to be crucial for cognition, cognitive deficits in schizophrenia may reflect PV neuron dysfunction in cortical neural circuits. Interestingly, it has been suggested that PV alterations in schizophrenia are the consequence of a hypofunction of signaling through N-methyl-D-aspartate (NMDA) receptors (NMDARs). Here, we review recent findings that address the question of how NMDAR hypofunction might produce deficits of PV neuron-mediated inhibition in schizophrenia. We conclude that while dysregulation of NMDARs may play an important role in the pathophysiology of schizophrenia, additional research is required to determine the particular cell type(s) that mediate dysfunctional NMDAR signaling in the illness.

Topics: Animals; Awareness; Cerebral Cortex; Cholecystokinin; Cognition Disorders; Cortical Synchronization; Electroencephalography; Glutamic Acid; Humans; Interneurons; Nerve Net; Neural Inhibition; Neuronal Plasticity; Neurons; Parvalbumins; Pyramidal Cells; Receptors, AMPA; Receptors, GABA; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Signal Transduction; Synaptic Transmission

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.

Topics: Animals; Aspartic Acid; Brain; Cholecystokinin; Disease Models, Animal; Dopamine; Entorhinal Cortex; gamma-Aminobutyric Acid; Genetic Linkage; Genetic Markers; Glutamic Acid; Humans; RNA, Messenger; Rodentia; Schizophrenia

It has been suggested that cholecystokinin (CCK), a gut-brain peptide found in high concentrations in the mammalian brain, might be implicated in the neurobiology of anxiety and panic disorder. The administration of CCK tetrapeptide induced panic attacks analogous to spontaneous ones in patients suffering from panic disorder and to a lesser degree in healthy volunteers. In animal models of anxiety, the pretreatment with CCK agonists and antagonists produced, respectively, anxiogenic- and anxiolytic-like action on the exploratory paradigms. On the other hand, CCK could also play a role in the pathophysiology of schizophrenia. The administration of CCK agonists (caerulein, CCK-8s) to rodents results in behavioural effects analogous to those of antipsychotic drugs. However, CCK agonists lack any activity in rodent behavioural models to reveal antipsychotic drugs. A significant reduction of CCK concentration and CCK receptors has been shown in cortical and limbic structures of patients suffering from schizophrenia. Nevertheless, administration of CCK agonists to these patients does not effect their symptoms. Two major conclusions should be drawn: first, CCK is involved in the neurobiology of anxiety; second, changes in the CCK system in schizophrenia could be linked to a cortical neurodegeneration related to this disease.

Topics: Animals; Anxiety Disorders; Ceruletide; Cholecystokinin; Humans; Neurotransmitter Agents; Receptors, Cholecystokinin; Schizophrenia; Sincalide

Topics: Animals; Anxiety; Brain; Cholecystokinin; Dopamine; Haloperidol; Humans; Neurons; Pyrazoles; Receptors, Cholecystokinin; Schizophrenia

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.

Topics: Cholecystokinin; Clinical Trials as Topic; Humans; Schizophrenia; Schizophrenic Psychology

Topics: Animals; Cholecystokinin; Dopamine; Electrophysiology; Humans; Mesencephalon; Models, Biological; Nucleus Accumbens; Rats; Schizophrenia; Sincalide; Synapses

Topics: Animals; Behavior, Animal; Cholecystokinin; Clinical Trials as Topic; Dopamine; Humans; Limbic System; Mesencephalon; Schizophrenia; Sincalide

Topics: Animals; Antipsychotic Agents; Brain; Cholecystokinin; Endorphins; gamma-Endorphin; Humans; Neuropeptides; Rats; Schizophrenia

The renaissance in postmortem studies in schizophrenia is in full bloom. Although there is no shortage of findings, there have been significant problems with replications and interpretations. Regardless, the postmortem approach remains a valid and promising one. Thus far, it has allowed for the testing of a number of hypotheses involving catecholamines, indoleamines, and neuropeptides in schizophrenia. It is hoped that new approaches, such as autoradiography and automated cell counting, will add new dimensions to postmortem studies of schizophrenia. If these studies can be coupled with premortem exams of patients, perhaps new inroads can be made in the understanding and treatment of the schizophrenic syndrome.

Topics: Acetylcholine; Brain; Brain Chemistry; Cholecystokinin; Dopamine; Endorphins; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Humans; Neurotensin; Neurotransmitter Agents; Norepinephrine; Peptides; Receptors, Adrenergic; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia; Serotonin; Substance P

Topics: Animals; Brain; Cholecystokinin; Dopamine; Humans; Mice; Neurons; Rats; Schizophrenia

Cholecystokinin (CCK), enkephalin, neurotensin (NT), substance P (SP) and substance K (SK) are five neuropeptides that exist in neuronal perikarya or fibers in the vicinity of the A10 dopamine neurons in the ventromedial mesencephalon. Based upon this anatomical proximity, many investigations have been evaluating the possibility that these peptides may influence the function of the A10 dopamine neurons. A variety of experimental techniques have been employed in this regard, including anatomical, electrophysiological, neurochemical and behavioral methodologies. Measurement of immunoreactive peptide levels with radioimmunoassay, and visualization of peptidergic neurons and fibers with immunocytochemistry has demonstrated not only that peptides exist in the vicinity of A10 dopamine neurons, but using double labeling techniques NT and CCK have been found to coexist with dopamine in the same neuron. Further, by combining retrograde tracing technique with immunocytochemistry, the origin of some peptidergic afferents to the ventromedial mesencephalon has been determined. With the exception of CCK-8, microinjection into the ventromedial mesencephalon of rats with all the peptides or potent analogues produces a dose-related increase in spontaneous motor activity. For SP, NT and enkephalin the motor response has been blocked by dopamine antagonists. Further, an increase in dopamine metabolism in mesolimbic dopamine terminal fields is produced concurrent with the behavioral hyperactivity. These data indicate that SP, SK, enkephalin and NT can activate dopamine neurons in the ventromedial mesencephalon. This postulate is supported by electrophysiological studies showing an excitatory action by iontophoretic administration of peptide onto dopamine neurons. However, in some studies, excitatory electrophysiological effects were not observed. While some observations are contradictory, sufficient data has accumulated that tentative postulates and conclusions can be made about how these peptides may influence the A10 dopamine neurons. Further, speculations are offered as to the role this modulatory action may play in the many behaviors and pathologies thought to involve these dopamine neurons.

Topics: Animals; Behavior, Animal; Cats; Cholecystokinin; Dopamine; Enkephalins; Haplorhini; Humans; Limbic System; Mesencephalon; Nerve Tissue Proteins; Neurokinin A; Neurotensin; Rats; Schizophrenia; Substance P; Swine

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.

Topics: Antipsychotic Agents; Ceruletide; Cholecystokinin; Dopamine; Humans; Neurotransmitter Agents; Receptors, Dopamine; Schizophrenia; Sincalide

Neurochemical postmortem examination of brain tissue may never be completely replaced as a research tool in psychiatry. This method has already provided support for the hypotheses relating norepinephrine, dopamine, serotonin, peptides, and hemisphere asymmetries to psychiatric syndromes.

Topics: Alcoholism; Alzheimer Disease; Brain Chemistry; Cholecystokinin; Depressive Disorder; Dopamine; Endorphins; gamma-Aminobutyric Acid; Humans; Limbic System; Mental Disorders; Norepinephrine; Opioid-Related Disorders; Receptors, Dopamine; Schizophrenia; Serotonin; Suicide

In Huntington's disease, there is a decrease of the neuropeptides, substance P, enkephalins, and cholecystokinin in the striatonigral system, whereas in Parkinson's disease an increase of substance P is found in the substantia nigra. Several neuropeptides should be involved in Alzheimer's disease: substance P, endorphins, vasopressin, ACTH, somatostatin, vasoactive intestinal peptide, cholecystokinin, neurotensin, delta sleep-inducing peptide. Alterations of substance P, vasoactive intestinal peptide, cholecystokinin, somatostatin, and endorphins may be related to the pathophysiology of schizophrenia. Delta sleep-inducing peptide may interfere in addiction pathology.

Topics: Alzheimer Disease; Brain Mapping; Central Nervous System Diseases; Cholecystokinin; Enkephalins; Humans; Huntington Disease; Limbic System; Nerve Tissue Proteins; Neurotransmitter Agents; Parkinson Disease; Schizophrenia; Substance P; Substance-Related Disorders

Topics: Aged; Alzheimer Disease; Animals; Brain; Cholecystokinin; Depressive Disorder; Endorphins; Female; Humans; Male; Mental Disorders; Middle Aged; Nerve Tissue Proteins; Neurotransmitter Agents; Schizophrenia; Substance P; Vasopressins

Cholecystokinin (CCK) gene and its receptors play an important role in several biological processes including satiety signaling. Administration of exogenous or endogenously secreted CCK leads to decreased food intake in both rats and humans. Similarly, in rats pretreated with intraperitoneal CCK, antagonists of the CCKA receptor prevent decrease in food intake. The CCKB receptor plays an important role in anxiety and gastric acid secretion. We investigated the role of polymorphisms in the CCK gene (2 SNPs) and its receptors CCKA (4 SNPs) and CCKB (4SNPs, 1 microsatellite, CTn) in antipsychotic induced weight gain (n=215). Weight change (%) from baseline was compared across genotypic groups using analysis of covariance. In the European ancestry patients treated with clozapine or olanzapine a trend of association was observed with the SNP rs2929183 (p=0.10) in CCKBR gene. Carriers of the genotype AA (3.23%±4.8) gained less weight than the AG and GG genotypes (6.50%±6.5; p=0.035). A similar trend was observed for the CTn repeat, where carriers of the LL genotype gained less weight (3.73%±5.41) than the S allele carrying genotypes (6.29%±6.2, p=0.05). In the subjects of African ancestry we observed similar marginal association although with the opposite allele. However, none of these observations would survive corrections for multiple testing. None of the other polymorphisms in either CCK or CCKA receptor genes was associated with weight change (%). In conclusion, CCKB receptor gene may play a role in antipsychotic induced weight gain. However, these observations need to be replicated in a larger and independent sample set.

Topics: Adolescent; Adult; Antipsychotic Agents; Cholecystokinin; Female; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Schizophrenia; Weight Gain; Young Adult

Immunoreactive-cholecystokinin (CCK) in cerebrospinal fluid (CSF) was examined in 11 drug-free DSM-III schizophrenic patients and 6 age-matched controls. CSF CCK was significantly lower (p less than .002) in schizophrenic subjects than in controls and was significantly lower (p less than .01) in male than female schizophrenic subjects. CSF CCK was significantly lower (p less than .04) in schizophrenic subjects whose antipsychotic response was delayed 28 or more days after initiation of haloperidol compared with earlier drug responders. CCK appears to be required for neuroleptic-induced depolarization-inactivation of dopamine neurons and associated antipsychotic response; therefore, schizophrenic patients with low CCK may be resistant to the antipsychotic effects of neuroleptics.

Topics: Adult; Cholecystokinin; Dopamine; Female; Haloperidol; Homovanillic Acid; Humans; Male; Neurons; Schizophrenia; Time Factors

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.

Topics: Cholecystokinin; Clinical Trials as Topic; Humans; Schizophrenia; Schizophrenic Psychology

Topics: Animals; Behavior, Animal; Cholecystokinin; Clinical Trials as Topic; Dopamine; Humans; Limbic System; Mesencephalon; Schizophrenia; Sincalide

Topics: Cholecystokinin; Humans; Schizophrenia

Cholecystokinin (CCK), a neuropeptide which fulfills almost all criteria for neurotransmitter status, has been co-localized with dopamine in midbrain mesolimbic and mesocortical neurons that have been implicated in the pathogenesis of schizophrenia. Preclinical research suggests that CCK may in part act to enhance central dopaminergic activity. In an attempt to evaluate the role of CCK relative to the dopamine hyperactivity hypothesis of schizophrenia, in the present investigation the putative CCK receptor antagonist, proglumide, was administered to four schizophrenic patients in a double-blind, placebo-controlled study. All patients were receiving concurrent neuroleptic medication, but were still significantly symptomatic. Proglumide was without effect on the patients' psychosis ratings. Potential reasons for this negative finding are discussed.

Topics: Adult; Cholecystokinin; Female; Glutamine; Humans; Pilot Projects; Proglumide; Schizophrenia

Topics: Adult; Aged; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Dopamine; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Schizophrenia

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.

Topics: Adult; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Cognition; Emotions; Female; Humans; Male; Receptors, Dopamine; Schizophrenia

Topics: Animals; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Feeding Behavior; Humans; Motor Activity; Parkinson Disease; Receptors, Dopamine; Schizophrenia; Sincalide; Synapses

Cholecystokinin (CCK) has been implicated as a neurotransmitter, and recent research has identified CCK as having potential antipsychotic effects in patients with chronic schizophrenia. Nine chronic schizophrenic patients with prominent psychotic symptoms and a history of resistance to conventional neuroleptic treatment were administered ceruletide, a synthetic decapeptide of cerulein, intramuscularly. No clinically significant short-term or long-term therapeutic effects were demonstrated, despite the results of statistical analysis which indicated significant improvement. The implications of this open clinical trial for a new treatment modality of chronic schizophrenia are discussed.

Topics: Adult; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Double-Blind Method; Humans; Injections, Intramuscular; Male; Middle Aged; Schizophrenia

Topics: Adult; Ceruletide; Cholecystokinin; Chronic Disease; Clinical Trials as Topic; Female; Humans; Long-Term Care; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Distinct components of working memory are coordinated by different classes of inhibitory interneurons in the PFC, but the role of cholecystokinin (CCK)-positive interneurons remains enigmatic. In humans, this major population of interneurons shows histological abnormalities in schizophrenia, an illness in which deficient working memory is a core defining symptom and the best predictor of long-term functional outcome. Yet, CCK interneurons as a molecularly distinct class have proved intractable to examination by typical molecular methods due to widespread expression of CCK in the pyramidal neuron population. Using an intersectional approach in mice of both sexes, we have succeeded in labeling, interrogating, and manipulating CCK interneurons in the mPFC. Here, we describe the anatomical distribution, electrophysiological properties, and postsynaptic connectivity of CCK interneurons, and evaluate their role in cognition. We found that CCK interneurons comprise a larger proportion of the mPFC interneurons compared with parvalbumin interneurons, targeting a wide range of neuronal subtypes with a distinct connectivity pattern. Phase-specific optogenetic inhibition revealed that CCK, but not parvalbumin, interneurons play a critical role in the retrieval of working memory. These findings shine new light on the relationship between cortical CCK interneurons and cognition and offer a new set of tools to investigate interneuron dysfunction and cognitive impairments associated with schizophrenia.

Topics: Animals; Appetitive Behavior; Cholecystokinin; Discrimination Learning; Discrimination, Psychological; Female; Genes, Reporter; Interneurons; Male; Memory, Short-Term; Mental Recall; Mice; Mice, Transgenic; Nerve Tissue Proteins; Odorants; Optogenetics; Parvalbumins; Patch-Clamp Techniques; Prefrontal Cortex; Reward; Schizophrenia; Smell; Synaptic Potentials

To investigate the polymorphism of cholecystokinin (CCK) gene -45C/T of schizophrenia and its application in forensic medicine.. Bidirectional allele specific PCR was used to detect CCK gene -45C/T polymorphisms in 207 schizophrenic patients (case group) and 202 healthy individuals (control group) of the Han population in northern China. The chi2 test was used to identify Hardy-Weinberg equilibrium of the genotype distribution in control group. The differences of genotype and allele frequencies distributions were compared between two groups.. Distributions of the genotype frequencies satisfied the law of Hardy-Weinberg equilibrium in control group. The differences between genotypic frequencies and allele frequencies were not statistical significance in case group and control groups (P > 0.05). Gender-stratified analysis showed that frequency of allele T in female case group was statistically higher than that in female control group (P = 0.044).. CCK gene -45C/T locus T allele may be positively associated with schizophrenia in female population and useful in schizophrenia identification.

Topics: Alleles; Asian People; Case-Control Studies; China; Cholecystokinin; Female; Forensic Genetics; Forensic Psychiatry; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Schizophrenia; Sequence Analysis, DNA

Tripeptidyl peptidase II (TPPII) is a high molecular weight exopeptidase important in inactivating extracellular cholecystokinin (CCK). Our aims were to study the anatomical localization of TPPII and CCK mRNA in the Cynomolgus monkey brain as a basis for a possible functional anatomical connection between enzyme (TPPII) and substrate (CCK) and examine if indications of changes in substrate availability in the human brain might be reflected in changes of levels of TPPII mRNA.. mRNA in situ hybridization on postmortem brain from patients having had a schizophrenia diagnosis as compared to controls and on monkey and rat brain slices.. overlapping distribution patterns of mRNAs for TPPII and CCK in rat and monkey. High amounts of TPPII mRNA are seen in the neocortex, especially in the frontal region and the hippocampus. TPPII mRNA is also present in the basal ganglia and cerebellum where CCK immunoreactivity and/or CCK B receptors have been found in earlier studies, suggesting presence of CCK-ergic afferents from other brain regions. Levels of mRNAs for CCK and TPPII show a positive correlation in postmortem human cerebral cortex Brodmann area (BA) 10. TPPII mRNA might be affected following schizophrenia.. overall TPPII and CCK mRNA show a similar distribution in rat and monkey brain, confirming and extending earlier studies in rodents. In addition, correlated levels of TPPII and CCK mRNA in human BA 10 corroborate a functional link between CCK and TPPII in the human brain.

Topics: Aminopeptidases; Animals; Cerebral Cortex; Cholecystokinin; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Gene Expression; Humans; Immunohistochemistry; In Situ Hybridization; Macaca fascicularis; Male; Postmortem Changes; Rats; RNA, Messenger; Schizophrenia; Serine Endopeptidases; Statistics, Nonparametric

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.

Topics: Alleles; Cholecystokinin; DNA; DNA Mutational Analysis; Gene Frequency; Genotype; Humans; Linkage Disequilibrium; Phenotype; Point Mutation; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Schizophrenia

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.

Topics: 5' Untranslated Regions; Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Base Sequence; Cholecystokinin; DNA; Female; Genotype; Humans; Linkage Disequilibrium; Male; Middle Aged; Molecular Sequence Data; Monte Carlo Method; Panic Disorder; Polymorphism, Genetic; Reference Values; Repetitive Sequences, Nucleic Acid; Schizophrenia

Microdialysis was employed to investigate the dopamine, cholecystokinin (CCK) and neurotensin receptor regulation of ventral striopallidal GABA transmission by intra-accumbens perfusion with selective receptor ligands and monitoring local or ipsilateral ventral pallidal GABA release. In the dual probe studies intra-accumbens perfusion with the dopamine D1 and D2 receptor agonists SKF28293 and pergolide had no effect on ventral pallidal GABA, while both the D1 and D2 receptor antagonists SCH23390 and raclopride increased ventral pallidal GABA release. In contrast, intra-accumbens CCK decreased ventral pallidal GABA release and this was reversed by local perfusion with the CCK2 receptor antagonist PD134308 but not the CCK1 receptor antagonist L-364,718. In a single probe study intra-accumbens neurotensin increased local GABA release, which was strongly potentiated when the peptidase inhibitor phosphodiepryl 08 was perfused together with neurotensin. In addition, the neurotensin receptor antagonist SR48692 counteracted this phosphodiepryl 08 induced potentiated increased in GABA release. Taken together, these findings indicate that mesolimbic dopamine and CCK exert a respective tonic and phasic inhibition of ventral pallidal GABA release while the antipsychotic activity associated with D1 and D2 receptor antagonists may be explained by their ability to increase ventral striopallidal GABA transmission. Furthermore, the findings suggest that CCK2 receptor antagonists and neurotensin endopeptidase inhibitors may be useful antipsychotics.

Topics: Animals; Cholecystokinin; Dopamine; Dopamine D2 Receptor Antagonists; Extracellular Space; gamma-Aminobutyric Acid; Globus Pallidus; Male; Microdialysis; Neural Inhibition; Neural Pathways; Neurons; Neurotensin; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Neurotensin; Schizophrenia; Synaptic Transmission

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.

Topics: Alleles; Alternative Splicing; Base Sequence; Bipolar Disorder; Cholecystokinin; Consensus Sequence; Disease Susceptibility; Exons; Genetic Linkage; Genotype; Humans; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Reference Values; Schizophrenia

Cholecystokinin (CCK), beta-endorphin (BE), and vasoactive intestinal peptide (VIP) in peripheral blood mononuclear cells from 30 drug-naive schizophrenics compared to 22 healthy controls were studied. Patients were evaluated with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of the Negative Symptoms (SANS) at baseline (TO), and after four weeks (T4) in nine patients who were subsequently treated with haloperidol (HL). Neuropeptide concentrations in peripheral blood mononuclear cells (PBMC) were measured at TO and, for the treated patients, at T4. There was a negative correlation between CCK and SANS baseline scores and a trend for patients who responded poorly to HL (i.e. patients with a prevalence of negative symptomatology) to have lower CCK basal values.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Behavioral Symptoms; beta-Endorphin; Case-Control Studies; Chi-Square Distribution; Cholecystokinin; Female; Haloperidol; Humans; Leukocytes, Mononuclear; Male; Neuropeptides; Regression Analysis; Schizophrenia; Severity of Illness Index; Treatment Outcome; Vasoactive Intestinal Peptide

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimer's disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Autopsy; Case-Control Studies; Cerebral Cortex; Cholecystokinin; Cognition; Corticotropin-Releasing Hormone; Dementia, Multi-Infarct; Female; Frontal Lobe; Humans; Male; Neuropeptides; Occipital Lobe; Schizophrenia; Schizophrenic Psychology; Somatostatin; Temporal Lobe; Vasoactive Intestinal Peptide

No consistent markers of pathology have been established yet in schizophrenia, although abnormalities in frontal and temporal structures are indicated from positron emission tomography (PET) studies. We have used in situ hybridization to investigate functional changes focusing on the quantitation of cholecystokinin (CCK) mRNA, whose product has been shown to be depleted in schizophrenia. CCK mRNA and G(o) alpha-subunit mRNA were measured in eight schizophrenic and eight control subjects matched for age and postmortem delay. The study revealed a marked decrease in CCK mRNA of 83% in frontal cortex (BA10) and 63% in superior temporal cortex (BA22) in schizophrenia with no change in G(o) alpha-subunit mRNA in either region. This study was extended to a further series of eight patients to determine the reproducibility of this effect and to quantitate laminar changes in CCK mRNA. Quantitation of CCK mRNA in inner cortical layers (layer V/VI) was carried out in frontal and temporal cortex in comparison with G(o) alpha-subunit mRNA, which is also concentrated in this region; this study showed a similar selective decrease in CCK mRNA in frontal and temporal cortex of 47% and 51%, respectively. A confirmatory decrease in CCK mRNA was also obtained by slot blot analysis of CCK mRNA in tissue extracts of frontal cortex by reference to levels of beta-tubulin mRNA, CCK mRNA:beta-tubulin mRNA was significantly decreased (67%) in schizophrenic tissue compared to control tissue. There was no significant correlation of CCK mRNA loss with neuroleptic treatment or duration of illness.

Topics: Adult; Aged; Aged, 80 and over; Cholecystokinin; Female; Frontal Lobe; Gene Expression; GTP-Binding Proteins; Humans; In Situ Hybridization; Male; Middle Aged; Prospective Studies; Reproducibility of Results; RNA, Messenger; Schizophrenia; Schizophrenic Psychology; Temporal Lobe; Tubulin

In human, cholecystokinin-immunoreactive nerve fibres are abundantly distributed in the ventral striatum and in other regions of the basal ganglia interconnected with the limbic system. This suggests that this neuropeptide is involved in the initiation of movements following emotional stimuli. The demonstration of an extended cholecystokinin expression in cortico-, thalamo-, and nigrostriatal pathways using in situ hybridization indicates that this neuromodulator may have some important functions either in motor, cognitive or limbic systems. In addition, disruption of the nigrostriatal dopaminergic pathway induces the expression of cholecystokinin in the striatal neurons. This new example of functional plasticity suggests that dopamine exerts a negative tonus on cholecystokinin expression. Finally, cholecystokinin expression is increased in meso-limbic and nigrostriatal dopaminergic neurons of schizophrenic patients.

Topics: Basal Ganglia; Cholecystokinin; Dopamine; Humans; In Situ Hybridization; Neural Pathways; Receptors, Cholecystokinin; RNA, Messenger; Schizophrenia

Neuropeptides, initially thought to be common features of gut and brain, are only synthesized in immune cells and modulate immune functions. The presence and possible functions of these peptides in immune cells in both physiological or pathological conditions have been investigated in our laboratory in the last years. Some of the data obtained are reviewed here, and future developments of the field are indicated.

Topics: Adult; Aged; Aged, 80 and over; Aging; Animals; beta-Endorphin; Brain; Chemotaxis; Cholecystokinin; Digestive System; Headache; Humans; Lymphocytes; Male; Middle Aged; Neuropeptides; Rats; Rats, Sprague-Dawley; Schizophrenia; Vasoactive Intestinal Peptide

Beta-endorphin, cholecystokinin and vasoactive intestinal peptide were measured in peripheral blood mononuclear cells of healthy controls, and schizophrenic patients at the first diagnosis before any treatment and after 2 or 15 d of treatment with haloperidol. Beta-endorphin concentrations were similar in controls and untreated patients, and increased with treatment. Cholecystokinin concentrations were higher in patients than in controls, and decreased during treatment. Vasoactive intestinal peptide was lower in patients and did not change with treatment. These observations are consistent with measurements of the same peptides in autopsy samples or cerebrospinal fluid. Peripheral blood mononuclear cells might be an useful tool for the study of some neuropeptides in brain.

Topics: Adolescent; Adult; beta-Endorphin; Cholecystokinin; Female; Haloperidol; Humans; Male; Monocytes; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Vasoactive Intestinal Peptide

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.

Topics: Adult; Aged; Autoradiography; Brain Mapping; Cholecystokinin; Female; Hippocampus; Humans; Male; Middle Aged; Receptors, Cholecystokinin; Schizophrenia; Schizophrenic Psychology; Temporal Lobe

Chronic administration of antipsychotic drugs has previously been shown to decrease the number of spontaneously active midbrain dopamine cells. In an effort to evaluate CCK antagonists as potential antipsychotic drugs, we have examined the effects of a selective CCK-B antagonist, LY262691, on the number of spontaneously active midbrain dopamine neurons using extracellular, single-unit recordings in anesthetized rats. Acute and chronic administration of LY262691 decreased the number of spontaneously active A9 and A10 dopamine cells. Administration of apomorphine did not reverse the effect of LY262691 on A9 and A10 dopamine neurons. These results suggest that LY262691 may have an antipsychotic effect without delayed onset, and that its effects on dopamine cells may not be mediated through depolarization inactivation.

Topics: Animals; Antipsychotic Agents; Apomorphine; Cholecystokinin; Dopamine; Male; Mesencephalon; Neurons; Pyrazoles; Rats; Rats, Inbred Strains; Schizophrenia

1. Cholecystokinin (CCK) is a neuropeptide which is co-localized within some mesolimbic and mesocortical dopamine neurons. 2. CCK resembles an antipsychotic drug in some pharmacological and behavioral tests. 3. Levels of CCK in the cerebrospinal fluid (CSF) are reduced in eleven drug-free schizophrenics in comparison with six controls. 4. Schizophrenic males have lower CSF CCK levels than females. 5. Rapidity of antipsychotic response to haloperidol appeared to be inversely related to drug-free baseline CSF CCK levels.

Topics: Adult; Cholecystokinin; Female; Haloperidol; Humans; Lithium; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Antidepressive Agents; Antipsychotic Agents; Brain; Cholecystokinin; Depressive Disorder; Endorphins; Humans; Neuropeptides; Neurotransmitter Agents; Schizophrenia

Topics: Autoradiography; Cholecystokinin; Fluorescent Antibody Technique; Humans; Mesencephalon; Receptors, Dopamine; RNA, Messenger; Schizophrenia

Neuroleptic-free schizophrenic patients received caerulein, a potent analogue of cholecystokinin octapeptide, in a fixed- and rising-dose schedule. In addition, neuroleptic-treated patients received a single dose of the peptide with a 4-week follow-up. No significant change in mental status was observed after any of these administration schedules. Peak plasma levels of caerulein were noted at 20-30 min after IM administration; at this time no changes in cortical evoked potential were demonstrated. Furthermore, levels of cholecystokinin were not found to be reduced, but were in fact elevated in lumbar cerebrospinal fluid of schizophrenic patients. These data argue against the antipsychotic efficacy of systemic caerulein administration and, because evidence of CNS response to CCK is lacking, suggest that other pharmacologic strategies may be necessary to effectively modify central peptide systems with systemically administered drugs.

Topics: Adult; Ceruletide; Cholecystokinin; Evoked Potentials; Humans; Male; Neurons; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Four neuropeptides (substance P, methionine-enkephalin, neurotensin and cholecystokinin) were measured by radioimmunoassays in a number of brain regions of deceased patients with mental illnesses and controls. The most striking finding in these studies was that methionine-enkephalin concentrations in caudate nuclei of chronic paranoid schizophrenic patients were reduced relative to several control groups. Neuroleptics had no obvious effects on any of the four measured neuropeptides. These findings are not inconsistent with the hypothesis that methionine-enkephalin may be involved in some of the pathology of the schizophrenic syndrome.

Topics: Adult; Aged; Alcoholism; Brain Chemistry; Cholecystokinin; Enkephalin, Methionine; Heroin Dependence; Humans; Mental Disorders; Middle Aged; Nerve Tissue Proteins; Neurotensin; Psychotic Disorders; Schizophrenia; Substance P; Suicide

Cerebrospinal fluid from 31 normals and two groups of phenomenologically similar schizophrenics (n = 72) were collected by identical methods. Radioimmunoassay of CSF was carried out for somatostatin, bombesin, and cholecystokinin. One group of schizophrenics had increased baseline somatostatin and cholecystokinin, and decreased bombesin. No CSF gradient effect was found for the peptides nor were their levels affected by probenecid or pimozide treatment. An inverse correlation was found between bombesin and psychosis rating. Intercorrelation between the peptides and HVA, 5-HIAA, and MHPG were not significant.

Topics: Adolescent; Adult; Bombesin; Cholecystokinin; Female; Humans; Hydrocortisone; Male; Middle Aged; Peptides; Pimozide; Probenecid; Schizophrenia; Somatostatin; Tryptophan

Topics: Animals; Anorexia Nervosa; Antipsychotic Agents; Apomorphine; Brain; Cholecystokinin; Glutamine; Humans; Mesencephalon; Neurons; Proglumide; Receptors, Dopamine; Schizophrenia

Topics: Animals; Cholecystokinin; Dopamine; Glutamates; Glutamic Acid; Humans; Nucleus Accumbens; Perfusion; Potassium; Proglumide; Receptors, Dopamine; Schizophrenia; Septal Nuclei

Topics: Cholecystokinin; Dopamine; Electroencephalography; Female; Humans; Limbic System; Male; Nerve Tissue Proteins; Radioimmunoassay; Receptors, Cell Surface; Receptors, Cholecystokinin; Schizophrenia

Concentrations of vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK) and gastrin in the cerebrospinal fluid (CSF) was studied in patients with endogenous depression, non-endogenous depression, mania, schizophrenia and a control group. All patients were classified according to various diagnostic systems. In the group of non-endogenously depressed patients CSF-VIP levels (median 16 pmol/l) were found significantly lowered compared to controls (median = 32 pmol/l) and endogenous depression (26 pmol/l). Going through the non-endogenous group it appeared that the low CSF-VIP was due to a group of patients with a former diagnosis of endogenous depression or a present diagnosis of possible endogenous depression. Moreover, this group was clinically characterized by 'dysphoric/hysterical features', 'reversed diurnal variation' (i.e. worst in the evening), and 'lack of clearly circumscribed episode'. In many aspects this group seems similar to the atypical depressions described as monoamineoxidase responders. Concerning CSF-CCK and CSF-gastrin no significant differences between the examined groups were demonstrated.

Topics: Adult; Aged; Arginine Vasopressin; Cholecystokinin; Depressive Disorder; Female; Humans; Male; Mental Disorders; Middle Aged; Nerve Tissue Proteins; Schizophrenia; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

Cholecystokinin (CCK) binding sites were assessed in post-mortem brain membrane preparations from controls and schizophrenic patients. 125I-BH CCK33 specific binding was reduced by 40% (p less than 0.02) in the hippocampus and by 20% (p less than 0.01) in the frontal cortex of schizophrenic patients compared with controls. There were no differences in 125I-BH CCK33 binding between the two groups in the amygdala, temporal cortex or caudate nucleus.

Topics: Adult; Aged; Amygdala; Binding Sites; Caudate Nucleus; Cerebral Cortex; Cholecystokinin; Female; Hippocampus; Humans; Male; Middle Aged; Schizophrenia

Topics: Animals; Antipsychotic Agents; Cholecystokinin; Humans; Rats; Schizophrenia; Schizophrenic Psychology

Vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK) and gastrin in the cerebrospinal fluid (CSF) were studied in patients with endogenous depression, non-endogenous depression, mania, schizophrenia and a control group. All patients were classified according to ICD-9 and the group of depressions was further classified according to the Newcastle Rating Scales for depression (Carney et al. 1965) (N-I). In the group of non-endogenously depressed patients, CSF-VIP levels (median 16 pmol/l) were found to be significantly lower than those of controls (median = 32 pmol/l) and endogenous depressives (36 pmol/l). In the non-endogenous group, it appeared that the low CSF-VIP was due to a group of patients who, during a past or present depressive episode, had been diagnosed as suffering from endogenous depression. Moreover, this group was clinically characterized by 'dysphoric/hysterical features', 'reversed diurnal variation' (i.e. worse in the evening), and 'lack of clearly circumscribed episodes'. In many aspects this group seems similar to the atypical depressives described as monoamine oxidase inhibitor responders. Concerning CSF-CCK and CSF-gastrin, no significant differences between the examined groups were demonstrated.

Topics: Adult; Aged; Bipolar Disorder; Cholecystokinin; Depressive Disorder; Female; Gastrins; Humans; Male; Middle Aged; Psychological Tests; Psychotic Disorders; Schizophrenia; Vasoactive Intestinal Peptide

The close relationship of cholecystokinin peptides with some of the dopamine pathways and the limbic system suggests a putative role for these peptides in the pathophysiology of neuropsychiatric disorders such as Parkinson's disease, manic-depression and schizophrenia. By use of radioimmunoassay, we report a significant decrease in cholecystokinin-immunoreactivity in the cerebrospinal fluid of patients with bipolar manic-depression and untreated schizophrenia in comparison to control subjects.

Topics: Adult; Bipolar Disorder; Cholecystokinin; Depressive Disorder; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Schizophrenia

Cholecystokinin-like immunoreactivity (CCK) and somatostatin-like immunoreactivity (SRIF) were determined in fourteen brains from patients dying with a diagnosis of schizophrenia and in twelve brains from control cases. The schizophrenics had been rated during life and were divided into two groups on the basis of the presence or absence of negative symptoms (affective flattening and poverty of speech). CCK was reduced in temporal cortex of the schizophrenics and in hippocampus and amygdala of those patients with negative symptoms. SRIF was reduced in the hippocampus in samples from the latter group. The selectivity of these changes to limbic lobe may reflect the presence of a degenerative process in that area. The association of changes in hippocampus and amygdala with negative symptoms of schizophrenia suggests a separate mechanism underlying these symptoms.

Topics: Aged; Amygdala; Brain; Cholecystokinin; Female; Hippocampus; Humans; Limbic System; Male; Middle Aged; Schizophrenia; Somatostatin

The human brain contains several peptides with probable synaptic actions, some of which form complex neuronal networks in the limbic lobe (amygdala, hippocampus and temporal cortex). A limbic lobe abnormality has been postulated in schizophrenia on the basis of similarities between schizophrenic symptoms and symptoms in cases of known limbic pathology. Cholecystokinin (CCK), somatostatin (SRIF), neurotensin (NT), vasoactive intestinal polypeptide (VIP) and substance P (SP)-like immunoreactivities were measured by radioimmunoassay in 10 brain areas of 14 schizophrenics and 12 controls. In the schizophrenic group symptoms had been rated in life and the group was divided into Type I (n = 7) and Type II (n = 7) subgroups on the basis of the absence or presence of morbid negative symptoms. In control brains each peptide showed a characteristic distribution with high levels in cortex (CCK), limbic lobe (SOM, NT, VIP) or striatal areas (SP) and low levels of each of the peptides in thalamus. Significant (P less than 0.05) differences between groups were: reductions of CCK and SOM in hippocampus and CCK in amygdala in Type II schizophrenics, and CCK in the temporal cortex of the total schizophrenic group; and elevations of VIP in amygdala in Type I schizophrenics and of SP in the hippocampus in the total schizophrenic group. The findings could not be explained by variables such as age, delay between death and necropsy or to neuroleptic medication. These clinical-state related alterations in the peptide content of the limbic system in schizophrenia may illuminate the pathophysiological basis of the disease, particularly the distinction between Type I and II syndromes.

Topics: Brain; Brain Chemistry; Cholecystokinin; Hormones; Humans; Limbic System; Neurotensin; Schizophrenia; Somatostatin; Substance P; Tissue Distribution; Vasoactive Intestinal Peptide

Topics: Animals; Apomorphine; Behavior, Animal; Brain; Bucladesine; Ceruletide; Cholecystokinin; Chronic Disease; Dopamine; Humans; Rats; Rats, Inbred Strains; Schizophrenia; Species Specificity

Immunoreactive somatostatin, bombesin, and cholecystokinin were measured in cerebrospinal fluid of normal subjects and patients with anorexia nervosa, depression, mania, and schizophrenia. Somatostatin-like immunoreactivity was decreased in anorexic and depressed patients. Bombesin-like immunoreactivity tended to be decreased in schizophrenics. Cholecystokinin-like immunoreactivity did not differ between groups. These data suggest a possible function for neuropeptides in regulation of human behavior.

Topics: Adult; Anorexia Nervosa; Bipolar Disorder; Bombesin; Cholecystokinin; Depressive Disorder; Female; Humans; Male; Mental Disorders; Peptides; Schizophrenia; Somatostatin

1. According to a currently popular biological hypothesis schizophrenic symptoms are caused by a hyperactivity in dopaminergic neurotransmission. Since cholecystokinin (CCK) is a neuromodulator of dopaminergic neurotransmission, the effects of CCK (0.3 microgram/kg; given in a single dose intravenously) were studied in six chronic paranoid schizophrenic patients. 2. Following 3 baseline assessments on separate days, the effects of CCK treatment were assessed immediately after the injection, daily for one week and weekly thereafter for 5 weeks by the Brief Psychiatric Rating Scale (BPRS) and by the Schizophrenia Subscale of the Present State Examination (SS-PSE). 3. One way analysis of variance revealed statistically significant changes in all BPRS factors as well as in the nuclear syndrome and in the total score of the SS-PSE. Dunnett's tests revealed that the time at which the changes from baseline became statistically significant was as follows: anxiety-depression factor of the BPRS, immediately after the injection; anergia factor of the BPRS, by day 2; thought disturbance factor of the BPRS, immediately after; activation factor of the BPRS, immediately after; hostile-suspiciousness factor of the BPRS, by day 1; total BPRS score, immediately after; nuclear syndrome of the SS-PSE, by day 1; and total score of the SS-PSE, by day 1. 4. It is concluded that further controlled studies of the antipsychotic properties of CCK are warranted.

Topics: Adult; Cholecystokinin; Chronic Disease; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) have been measured, by radioimmunoassay, in cerebral cortex obtained at autopsy from patients without neurological or psychiatric disease and from patients with Alzheimer's disease, depression and schizophrenia. Sephadex gel filtration indicated that over 90% of the CCK immunoreactivity was associated with the octapeptide in extracted material from the different clinical groups investigated. There were no significant differences from the normal in the overall concentrations of either VIP or CCK in any of the psychiatric groups examined, although differences in Alzheimer's disease were apparent when cases were grouped according to postmortem delay.

Topics: Alzheimer Disease; Cerebral Cortex; Cholecystokinin; Dementia; Depressive Disorder; Gastrointestinal Hormones; Humans; Radioimmunoassay; Schizophrenia; Synaptic Transmission; Vasoactive Intestinal Peptide