cholecystokinin and Depressive-Disorder

Depression is the second leading cause of disability in the world population, for which currently available pharmacological therapies either have poor efficacy or have some adverse effects. Accumulating evidence from clinical and preclinical studies demonstrates that the amygdala is critically implicated in depressive disorders, though the underlying pathogenesis mechanism needs further investigation. In this literature review, we overviewed depression and the key role of Gamma-aminobutyric acid (GABA) and Glutamate neurotransmission in depression. Notably, we discussed a new cholecystokinin-dependent plastic changes mechanism under stress and a possible antidepressant response of cholecystokinin B receptor (CCKBR) antagonist. Moreover, we discussed the fundamental role of the amygdala in depression, to discuss and understand the pathophysiology of depression and the inclusive role of the amygdala in this devastating disorder.

Topics: Amygdala; Cholecystokinin; Depression; Depressive Disorder; gamma-Aminobutyric Acid; Humans; Synaptic Transmission

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

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

Levels of cholecystokinin (CCK) peptides were measured in the CSF from 105 patients suffering from major depressive disorders admitted to a research psychiatric ward for diagnostic evaluation, by a radioimmunoassay method using two different antibodies. Relations between CCK levels and parameters of depression, anxiety, and suicidal behaviour were investigated. Significant inverse correlations were found between CCK levels and certain depression and anxiety parameters. Patients who had made one or more suicide attempts tended to have higher CSF CCK levels than those who had not. No correlations were found between CSF CCK and 5-HIAA or HVA, or with plasma cortisol.

Topics: Adult; Aged; Anxiety; Blood Glucose; Cholecystokinin; Depressive Disorder; Female; Homovanillic Acid; Humans; Hydrocortisone; Hydroxyindoleacetic Acid; Male; Middle Aged; Radioimmunoassay; Suicide

Stress can alter the number and morphology of excitatory synapses in the hippocampus, but nothing is known about the effect of stress on inhibitory synapses. Here, we used an animal model for depression, the chronic mild stress model, and quantified the number of perisomatic inhibitory neurons and their synapses. We found reduced density of parvalbumin-positive (PV+) neurons in response to stress, while the density of cholecystokinin-immunoreactive (CCK+) neurons was unaffected. We did a detailed electron microscopic analysis to quantify the frequency and morphology of perisomatic inhibitory synapses in the hippocampal CA1 area. We analyzed 1100 CA1 pyramidal neurons and 4800 perisomatic terminals in five control and four chronically stressed rats. In the control animals we observed the following parameters: Number of terminals/soma = 57; Number of terminals/100 µm cell perimeter = 10; Synapse/terminal ratio = 32%; Synapse number/100 terminal = 120; Average terminal length = 920nm. None of these parameters were affected by the stress exposure. Overall, these data indicate that despite the depressive-like behavior and the decrease in the number of perisomatic PV+ neurons in the light microscopic preparations, the number of perisomatic inhibitory synapses on CA1 pyramidal cells was not affected by stress. In the electron microscope, PV+ neurons and the axon terminals appeared to be normal and we did not find any apoptotic or necrotic cells. This data is in sharp contrast to the remarkable remodeling of the excitatory synapses on spines that has been reported in response to stress and depressive-like behavior. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Topics: Animals; CA1 Region, Hippocampal; Cell Count; Cholecystokinin; Depressive Disorder; Disease Models, Animal; Immunohistochemistry; Male; Microscopy, Electron; Neural Inhibition; Parvalbumins; Presynaptic Terminals; Pyramidal Cells; Rats, Wistar; Stress, Psychological; Synapses

Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Brain Mapping; Cholecystokinin; Chronic Disease; Depressive Disorder; Indoles; Limbic System; Male; Meglumine; Mice; Mice, Inbred C57BL; Neural Pathways; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Receptor, Cholecystokinin B; Social Dominance; Stress, Psychological

In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD).. The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42).. From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively).. The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD.

Topics: Cholecystokinin; Comorbidity; Depressive Disorder; DNA; DNA Primers; Genotype; Humans; Oligonucleotide Array Sequence Analysis; Panic Disorder; Polymorphism, Genetic; Receptors, Dopamine; Receptors, Serotonin; Reference Values

Cholecystokinin (CCK), a neurotransmitter in the central nervous system (CNS), co-exists in a large portion of A10 dopamine neurons to exert some effect on dopamine behavior. The aim of this study was to determine whether any association exists between the genotype of CCK gene promoter regions (-45C/T and -196G/A) and suicidal behavior. Genotypes and allele frequencies of CCK -45C/T and -196G/A were analyzed using polymerase chain reaction (PCR) followed by single-strand conformational polymorphism (SSCP) analysis on the genomic DNA from selected suicide victims (N=154) and from control subjects (N=328). Statistical analysis was performed using the Mantel-Haesnzel chi2-test and multiple logistic regression analysis with distinction of gender. An association between CCK -196G/A polymorphism and suicidal behavior in Japanese males was confirmed by statistical analysis (Odds ratio: 3.462, 95% CI: 1.128-10.626, P=0.038 by multiple logistic regression analysis). However, a significant association between CCK -196G/A polymorphism and suicidal behavior was not discovered in females. The polymorphism of the CCK gene promoter region was found to represent a susceptibility factor for suicidal behavior in Japanese males.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Cholecystokinin; Depressive Disorder; DNA Primers; Female; Humans; Japan; Logistic Models; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic; Suicide

Very little is known about the physiologic significance of the gut-brain hormone cholecystokinin (CCK) in the human central nervous system, although the hormone has been hypothesized to be involved in the regulation of both appetite and anxiety. We continuously collected lumbar cerebrospinal fluid (CSF) via indwelling subarachnoid catheters in ten normal volunteers, ten patients with major depression and five abstinent alcoholic humans, while fasting and after eating. Five other healthy subjects were fasted throughout the experiment. We quantified CSF immunoreactive cholecystokinin (IR-CCK) and glucose concentrations at 10-min intervals from 11.00 to 17.00 h. No difference in CSF IR-CCK concentration, half-life or rhythm was observed between normal volunteers and either depressed or alcoholic patients. Fasting CSF IR-CCK concentrations were 1.3 +/- 0.18, 1.3 +/- 0.21 and 1.2 +/- 0.21 fmol/ml (mean +/- S.E.M.) in normal volunteers, depressed patients and alcoholic patients, respectively. After eating, CSF IR-CCK concentrations rose to 1.5 +/- 0.21, 1.5 +/- 0.24 and 1.4 +/- 0.26 fmol/ml, respectively. Normal volunteers who did not eat had similar basal CSF IR-CCK concentrations (1.1 +/- 0.1 fmol/ml) which similarly rose to 1.4 +/- 0.13 fmol/ml during the sampling interval. In contrast, CSF glucose concentrations rose only in the subjects who ate, beginning to rise after about 1 h and remaining elevated for at least 3 h after eating. These data suggest the existence of a diurnal rhythm of IR-CCK release into CSF, as opposed to a response to feeding. The disappearance half-time of CCK in human CSF is less than 13 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alcoholism; Cholecystokinin; Chromatography, Gel; Depressive Disorder; Eating; Fasting; Female; Glucose; Half-Life; Humans; Male; Melanocyte-Stimulating Hormones; Middle Aged; Radioimmunoassay; Temperance

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

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

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

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